Amide derivatives as inhibitors of matrix metalloproteinases, TNF-α, and aggrecanase

ABSTRACT

The present application describes novel amides and derivatives thereof of formula I:                    
     or pharmaceutically acceptable salt forms thereof, wherein these compounds are useful as inhibitors of matrix metalloproteinases, TNF-α, and aggrecanase.

This application claims benefit of Provisional Application Ser. No.60/127,635 filed Apr. 2, 1999.

FIELD OF THE INVENTION

This invention relates generally to novel amide derivatives asinhibitors of matrix metalloproteinases, TNF-α, and aggrecanase,pharmaceutical compositions containing the same, and methods of usingthe same.

BACKGROUND OF THE INVENTION

There is now a body of evidence that metalloproteinases (MP) areimportant in the uncontrolled breakdown of connective tissue, includingproteoglycan and collagen, leading to resorption of the extracellularmatrix. This is a feature of many pathological conditions, such asrheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration;tumor metastasis or invasion; periodontal disease and bone disease.Normally these catabolic enzymes are tightly regulated at the level oftheir synthesis as well as at their level of extracellular activitythrough the action of specific inhibitors, such as α-2-macroglobulinsand TIMP (tissue inhibitor of metalloproteinase), which form inactivecomplexes with the MP's.

Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructivediseases of articular cartilage characterized by localized erosion ofthe cartilage surface. Findings have shown that articular cartilage fromthe femoral heads of patients with OA, for example, had a reducedincorporation of radiolabeled sulfate over controls, suggesting thatthere must be an enhanced rate of cartilage degradation in OA (Mankin etal. J. Bone Joint Surg. 1970, 52A, 424-434). There are four classes ofprotein degradative enzymes in mammalian cells: serine, cysteine,aspartic and metalloproteinases. The available evidence supports that itis the metalloproteinases which are responsible for the degradation ofthe extracellular matrix of articullar cartillage in OA and RA.Increased activities of collagenases and stromelysin have been found inOA cartilage and the activity correlates with severity of the lesion(Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner et al.Arthritis Rheum. 1983, 26, 63-68 and Ibid. 1984, 27, 305-312). Inaddition, aggrecanase (a newly identified metalloproteinase enzymaticactivity) has been identified that provides the specific cleavageproduct of proteoglycan, found in RA and OA patients (Lohmander et al.Arthritis Rheum. 1993, 36, 1214-22).

Therefore metalloproteinases (MP) have been implicated as the keyenzymes in the destruction of mammalian cartilage and bone. It can beexpected that the pathogenesis of such diseases can be modified in abeneficial manner by the administration of MP inhibitors, and manycompounds have been suggested for this purpose (see Wahl et al. Ann.Rep. Med. Chem. 1990, 25, 175-184, AP, San Diego).

Tumor necrosis factor (TNF) is a cell associated cytokine that isprocessed from a 26 kd precursor form to a 17 kd active form. TNF hasbeen shown to be a primary mediator in humans and in animals, ofinflammation, fever, and acute phase responses, similar to thoseobserved during acute infection and shock. Excess TNF has been shown tobe lethal. There is now considerable evidence that blocking the effectsof TNF with specific antibodies can be beneficial in a variety ofcircumstances including autoimmune diseases such as rheumatoid arthritis(Feldman et al, Lancet, 1994, 344, 1105) and non-insulin dependentdiabetes melitus. (Lohmander et al. Arthritis Rheum. 1993, 36, 1214-22)and Crohn's disease (MacDonald et al. Clin. Exp. Immunol. 1990, 81,301).

Compounds which inhibit the production of TNF are therefore oftherapeutic importance for the treatment of inflammatory disorders.Recently it has been shown that a matrix metalloproteinase or family ofmetalloproteinases, hereafter known as TNF-convertases (TNF-C), as wellas other MP's are capable of cleaving TNF from its inactive to activeform (Gearing et al Nature, 1994, 370, 555). This invention describesmolecules that inhibit this conversion and hence the secretion of activeTNF-a from cells. These novel molecules provide a means of mechanismbased therapeutic intervention for diseases including but not restrictedto septic shock, haemodynamic shock, sepsis syndrom, post ischaemicreperfusion injury, malaria, Crohn's disease, inflammatory boweldiseases, mycobacterial infection, meningitis, psoriasis, congestiveheart failure, fibrotic diseases, cachexia, graft rejection, cancer,diseases involving angiogenesis, autoimmune diseases, skin inflammatorydiseases, osteo and rheumatoid arthritis, multiple sclerosis, radiationdamage, hyperoxic alveolar injury, periodontal disease, HIV andnon-insulin dependent diabetes melitus.

Since excessive TNF production has been noted in several diseaseconditions also charactarized by MMP-mediated tissue degradation,compounds which inhibit both MMPs and TNF production may also have aparticular advantage in diseases where both mechansisms are involved.

There are several patents which disclose hydroxamate and carboxylatebased MMP inhibitors.

WO95/09841 describes compounds that are hydroxamic acid derivatives andare inhibitors of cytokine production.

EP 574,758 A1 depicts hydroxamic acid derivatives as collagenaseinhibitors having the general formula:

GB 2,268,934 A and WO94/24140 claim hydroxamate inhibitors of MMPs asinhibitors of TNF production.

WO97/08133 portrays compounds, for treating inflammatory diseases, ofthe formula:

wherein Ring M is an aromatic ring, cycloalkylene or a divalentheterocycle. Compounds of this sort art not considered to be included inthe present invention.

The compounds of the current invention act as inhibitors of MMPs,aggrecanase and/or TNF. These novel molecules are provided asanti-inflammatory compounds and cartilage protecting therapeutics. Theinhibiton of aggrecanase, TNF-C, and other metalloproteinases bymolecules of the present invention indicates they are anti-inflammatoryand should prevent the degradation of cartilage by these enzymes,thereby alleviating the pathological conditions of osteo- and rheumatoidarthritis.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novelamides which are useful as metalloprotease inhibitors orpharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

It is another object of the present invention to provide a method fortreating inflammatory disorders comprising administering to a host inneed of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or a pharmaceuticallyacceptable salt or prodrug form thereof.

It is another object of the present invention to provide novel compoundsfor use in therapy.

It is another object of the present invention to provide the use ofnovel compounds for the manufacture of a medicament for the treatment ofa condition or disease mediated by MMPs, TNF, aggrecanase, or acombination thereof.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat compounds of formula (I):

or pharmaceutically acceptable salt or prodrug forms thereof, wherein A,B, C, R¹, R², R³, and R⁴ are defined below, are effectivemetalloprotease inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Thus, in an embodiment, the present invention provides a novel compoundof formula I:

or a stereoisomer or pharmaceutically acceptable salt form thereof,wherein;

A is selected from COR⁵, —CO₂H, —CO₂R⁶, —CONHOH, —CONHOR⁵, —CONHOR⁶,—NHR^(a), —N(OH)COR⁵, —SH, —CH₂SH, —SONHR^(a), SN₂H₂R^(a),—S(O)(═NH)R^(a), —S(═NH)₂R^(a), PO(OH)₂, and PO(OH)NHR^(a);

R¹ is selected from H, Q, C₁₋₁₀ alkylene-Q, C₂₋₁₀ alkenylene-Q, C₂₋₁₀alkynylene-Q, (CRR′)_(r′)O(CRR′)_(r)—Q, (CRR′)_(r′)NR^(a)(CRR′)_(r)—Q,(CRR′)_(r′)C(O)(CRR′) _(r)—Q, (CRR′)_(r′)C(O)O(CRR′)_(r)—Q,(CRR′)_(r′)OC(O)(CRR′)_(r)—Q, (CRR′)_(r′)C(O)NR^(a)(CRR′)_(r)—Q,(CRR′)_(r′)NR^(a)C(O)(CRR′)_(r)—Q, (CRR′)_(r′)OC(O)O(CRR′)_(r)—Q,(CRR′)_(r′)OC(O)NR^(a)(CRR′)_(r)—Q, (CRR′)_(r′)NR^(a)C(O)O(CRR′)_(r)—Q,(CRR′)_(r′)NR^(a)C(O)NR^(a)(CRR′)_(r)—Q,(CRR′)_(r′)S(O)_(p)(CRR′)_(r)—Q, (CRR′)_(r′)SO₂NR^(a)(CRR′)_(r)—Q,(CRR′)_(r′)NR^(a)SO₂(CRR′)_(r)—Q,(CRR′)_(r′)NR^(a)SO₂NR^(a)(CRR′)_(r)—Q,(CRR′)_(r′)NR^(a)C(O)(CRR′)_(r″)NHQ,(CRR′)_(r′)NR^(a)C(O)(CRR′)_(r)NHC(O)OR^(a), and(CRR′)_(r′)NR^(a)C(O)(CRR′)_(r)NHC(O)(CRR′)_(r)NHC(O)OR^(a);

alternatively, R¹ and R^(b′) taken together with the CR²—N to which theyare attached form a 4-8 membered cyclic amine containing from 0-1 doublebonds, 0-1 S(O)_(p), O-1 oxygen atoms, and 0-1 NR^(a), and substitutedwith 0-1 groups selected from OH and ═O and is substituted with 0-3R^(b);

R′, at each occurrence, is independently selected from H, CH₃, CH₂CH₃,CH(CH₃)₂, CH═CH₂, CH═CHCH₃, and CH₂CH═CH₂;

R′, at each occurrence, is independently selected from H, CH₃, CH₂CH₃,and CH(CH₃)₂;

alternatively, R and R′ together with the carbon to which they areattached form a cyclopropyl, cyclobutyl or cyclopentyl group;

Q, at each occurence, is selected from H, a C₃₋₁₃ carbocyclic residuesubstituted with 0-5 R^(c) and a 5-14 membered heterocyclic systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S and substituted with 0-5 R^(c);

R² is selected from H, C₁₋₁₀ alkylene-H, C₂₋₁₀ alkenylene-H, C₂₋₁₀alkynylene-H, (CRR′)_(r′)O(CRR′)_(r)—H, (CRR′)_(r′)NR^(a)(CRR′)_(r)—H,(CRR′)_(r′)C(O)(CRR′) _(r)—H, (CRR′)_(r′)C(O)O(CRR′)_(r)—H,(CRR′)_(r′)OC(O)(CRR′)_(r)—H, (CRR′)_(r′)C(O)NR^(a)(CRR′)_(r)—H,(CRR′)_(r′)NR^(a)C(O)(CRR′)_(r)—H, (CRR′)_(r′)OC(O)O(CRR′)_(r)—H,(CRR′)_(r′)OC(O)NR^(a)(CRR′)_(r)—H, (CRR′)_(r′)NR^(a)C(O)O(CRR′)_(r)—H,(CRR′)_(r′)NR^(a)C(O)NR^(a)(CRR′)_(r)—H,(CRR′)_(r′)S(O)_(p)(CRR′)_(r)—H, (CRR′)_(r′)SO₂NR^(a)(CRR′)_(r)—H,(CRR′)_(r′)NR^(a)SO₂(CRR′)_(r)—H, and(CRR′)_(r′)NR^(a)SO₂NR^(a)(CRR′)_(r)—H;

R³ is U—X—Y—Z—U^(a)—X^(a)—Y^(a)—X¹—Z^(a);

U is absent or is selected from: O, NR^(a), C(O), C(O)O, OC(O),C(O)NR^(a), NR^(a)C(O), OC(O)O, OC(O)NR^(a), NR^(a)C(O)O,NR^(a)C(O)NR^(a), S(O)_(p), S(O)_(p)NR^(a), NR^(a)S(O)_(p), andNR^(a)SO₂NR^(a);

X is absent or selected from C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, and C₂₋₁₀alkynylene;

Y is absent or selected from O, NR^(a), S(O)_(p), S(O)_(p)NR^(a),C(O)NR^(a), and C(O), provided that when U and Y are present, X ispresent;

Z is absent or selected from a C₃₋₁₃ carbocyclic residue substitutedwith 0-5 R^(d) and a 5-14 membered heterocyclic system containing from1-4 heteroatoms selected from the group consisting of N, O, and S andsubstituted with 0-5 R^(d);

U^(a) is absent or is selected from: O, NR^(a), C(O), C(O)O, OC(O),C(O)NR^(a), NR^(a)C(O), OC(O)O, OC(O)NR^(a), NR^(a)C(O)O,NR^(a)C(O)NR^(a), S(O)_(p), S(O)_(p)NR^(a), NR^(a)S(O)_(p), andNR^(a)SO₂NR^(a);

X^(a) is absent or selected from C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, andC₂₋₁₀ alkynylene;

Y^(a) is absent or selected from O, NR^(a), S(O)_(p), S(O)_(p)NR^(a),C(O)NR^(a), and C(O), provided that when U^(a) and Y^(a) are present,X^(a) is present;

X¹ is absent or selected from C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, andC₂₋₁₀ alkynylene;

Z^(a) is selected from H, a C₃₋₁₃ carbocyclic residue substituted with0-5 R^(d) and a 5-14 membered heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and S andsubstituted with 0-5 R^(d);

R⁴ is selected from H, Q′, C₁₋₁₀ alkylene-Q′, C₂₋₁₀ alkenylene-Q′, C₂₋₁₀alkynylene-Q′, (CRR′)_(r′)O(CRR′)_(r)—Q′,(CRR′)_(r′)NR^(a)(CRR′)_(r)—Q′, (CRR′)_(r′)NR^(a)C(O)(CRR′)_(r)—Q,(CRR′)_(r′)C(O)NR^(a)(CRR′)_(r)—Q′, (CRR′)_(r′)C(O)(CRR′)_(r)—Q′,(CRR′)_(r′)C(O)O(CRR′)_(r)—Q′, (CRR′)_(r′)S(O)_(p)(CRR′)_(r)—Q′,(CRR′)_(r′)SO₂NR^(a)(CRR′)_(r)—Q′,(CRR′)_(r′)NR^(a)C(O)NR^(a)(CRR′)_(r)—Q′,(CRR′)_(r′)OC(O)NR^(a)(CRR′)_(r)—Q′, and(CRR′)_(r′)NR^(a)C(O)O(CRR′)_(r)—Q′;

R⁴a is selected from H, C₁₋₆ alkyl, —C₁₋₆ alkyl-phenyl, and phenyl;

alternatively, R⁴ and R^(4a), together with the carbon to which they areattached, combine to form a 3-8 membered carbocyclic ring substitutedwith 0-3 R^(b) or a 3-8 membered heterocyclic ring containing from 1-3heteroatoms selected from N, O, and S(O)_(p) and substituted with 0-3R^(b);

Q′ is selected from H, a C₃₋₁₃ carbocyclic residue substituted with 0-5R^(b) and a 5-14 membered heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and S andsubstituted with 0-5 R^(b);

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,phenyl or benzyl;

R^(a′), at each occurrence, is independently selected from H, C₁₋₄alkyl, phenyl or benzyl;

R^(a″), at each occurrence, is independently selected from C₁₋₄ alkyl,phenyl or benzyl;

alternatively, R^(a) and R^(a′) taken together with the nitrogen towhich they are attached form a 4, 5, or 6 membered ring containing from0-1 additional heteroatoms selected from the group consisting of N, O,and S;

R^(b) is selected from H, C₁₋₆ alkyl, phenyl, benzyl, C(O)R^(a),C(O)NR^(a)R^(a′), S(O)₂NR^(a)R^(a′), and S(O)_(p)R^(a″);

R^(b′) is selected from H, Q, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q, C₂₋₆alkynylene-Q, (CRR′)^(r′)O(CRR′)_(r)—Q, (CRR′)_(r′)NR^(a)(CRR′)_(r)—Q,(CRR′)_(r′)C(O)(CRR′) _(r)—Q, (CRR′)_(r′)C(O)O(CRR′)_(r)—Q, (CRR′)_(r′),OC(O)(CRR′)_(r)—Q, (CRR′)_(r′)C(O)NR^(a)(CRR′)_(r)—Q,(CRR′)_(r′)NR^(a)C(O)(CRR′)_(r)—Q, (CRR′)_(r′)OC(O)O(CRR′)_(r)—Q,(CRR′)_(r′)OC(O)NR^(a)(CRR′)_(r)—Q, (CRR′)_(r′)NR^(a)C(O)O(CRR′)_(r)—Q,(CRR′)_(r′)NR^(a)C(O)NR^(a)(CRR′)_(r)—Q,(CRR′)_(r′)S(O)_(p)(CRR′)_(r)—Q, (CRR′)_(r′)SO₂NR^(a)(CRR′)_(r)—Q,(CRR′)_(r′)NR^(a)SO₂(CRR′)_(r)—Q, and (CRR′)_(r′)NR^(a)SO₂NR^(a)(CRR′)_(r)—Q;

R^(c), at each occurrence, is independently selected from C₁₋₆ alkyl,OR^(a), Cl, F, Br, I, ═O, CN, NO₂, NR^(a)R^(a′), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a′), NR^(a)C(O)NR^(a)R^(a′), OC(O)NR^(a)R^(a′),R^(a)NC(O)O, S(O)₂NR^(a)R^(a′), NR^(a)S(O)₂R^(a″), NR^(a)S(O)₂NR^(a)R^(a′), OS(O)₂NR^(a)R^(a′), NR^(a)S(O)₂O, S(O)_(p)R^(a″), CF₃,CF₂CF₃, —CH(═NOH), —C(═NOH)CH₃, (CRR′)_(s)O(CRR′)_(s′)R^(c′),(CRR′)_(s)S(O)_(p)(CRR′)_(s′)R^(c′), (CRR′)_(s)NR^(a)(CRR′)_(s′)R^(c′),C₃₋₁₀ carbocyclic residue and a 5-14 membered heterocyclic systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S;

R^(c′), at each occurrence, is independently selected from phenylsubstituted with 0-3 R^(b), biphenyl substituted with 0-2 R^(b),naphthyl substituted with 0-3 R^(b) and a 5-10 membered heteroarylsystem containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S and substituted with 0-3 R^(b);

R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl,OR^(a), Cl, F, Br, I, ═O, CN, NO₂, NR^(a)R^(a′), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a′), NR^(a)C(O)NR^(a)R^(a′), OC(O)NR^(a)R^(a′),NR^(a)C(O)O, S(O)₂NR^(a)R^(a′), NR^(a)S(O)₂R^(a″),NR^(a)S(O)₂NR^(a)R^(a′), OS(O)₂NR^(a)R^(a′), NR^(a)S(O)₂O,S(O)_(p)R^(a″), CF₃, CF₂CF₃, C₃₋₁₀ carbocyclic residue and a 5-14membered heterocyclic system containing from 1-4 heteroatoms selectedfrom the group consisting of N, O, and S;

R⁵, at each occurrence, is selected from H, C₁₋₁₀ alkyl substituted with0-2 R^(e), and C₁₋₈ alkyl substituted with 0-2 R^(f);

R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl,OR^(a), Cl, F, Br, I, ═O, CN, NO₂, NR^(a)R^(a′), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a′), S(O)₂NR^(a)R^(a′), S(O)_(p)R^(a″), CF₃, and CF₂CF₃;

R^(f), at each occurrence, is selected from phenyl substituted with 0-2R^(e) and biphenyl substituted with 0-2 R^(e);

R⁶, at each occurrence, is selected from phenyl, naphthyl, C₁₋₁₀alkyl-phenyl-C₁₋₆ alkyl-, C₃₋₁₁ cycloalkyl, C₁₋₆ alkylcarbonyloxy-C₁₋₃alkyl-, C₁₋₆ alkoxycarbonyloxy-C₁₋₃ alkyl-, C₂₋₁₀ alkoxycarbonyl, C₃₋₆cycloalkylcarbonyloxy-C₁₋₃ alkyl-, C₃₋₆ cycloalkoxycarbonyloxy-C₁₋₃alkyl-, C₃₋₆ cycloalkoxycarbonyl, phenoxycarbonyl,phenyloxycarbonyloxy-C₁₋₃ alkyl-, phenylcarbonyloxy-C₁₋₃ alkyl-, C₁₋₆alkoxy-C₁₋₆ alkylcarbonyloxy-C₁₋₃ alkyl-, [5-(C₁-C5alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, -C₁₋₁₀ alkyl-NR⁷R^(7a),—CH(R⁸)OC(═O)R⁹,—CH(R⁸)OC(═O)OR⁹, and

R⁷ is selected from H and C₁₋₁₀ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-;

R^(7a) is selected from H and C₁₋₁₀ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-;

R⁸ is selected from H and C₁₋₄ linear alkyl;

R⁹ is selected from H, C₁₋₈ alkyl substituted with 1-2 R^(g), C₃₋₈cycloalkyl substituted with 1-2 R^(g), and phenyl substituted with 0-2R^(e);

R^(g), at each occurrence, is selected from C₁₋₄ alkyl, C₃₋₈ cycloalkyl,C₁₋₅ alkoxy, phenyl substituted with 0-2 R^(e);

p, at each occurrence, is selected from 0, 1, and 2;

r, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,and 10;

r′, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,and 10; and,

s, at each occurrence, is selected from 0, 1, 2, and 3.

In a preferred embodiment, the present invention provides compounds,wherein:

A is selected from COR⁵, —CO₂H, —CONHOH, —CONHOR⁵, —CONHOR⁶, —N(OH)COR⁵,—SH, and —CH₂SH;

R¹ is selected from H, C₁₋₁₀ alkylene-Q, C₂₋₁₀ alkenylene-Q, C₂₋₁₀alkynylene-Q, (CH₂)^(r′)O(CH₂)_(r)—Q, (CH₂)_(r′)NR^(a)(CH₂)_(r)—Q,(CH₂)_(r′)C(O) (CH₂)_(r)—Q, (CRR′)_(r′)C(O)O(CRR′)_(r)—Q,(CH₂)_(r′)C(O)NR^(a)(CH₂)_(r)—Q, (CH₂)_(r′)NR^(a)C(O)(CH₂)_(r)—Q,(CH₂)_(r′)OC(O)NR^(a)(CH₂)_(r)—Q, (CH₂)_(r′)NR^(a)C(O)O(CH₂)_(r)—Q,(CH₂)_(r′)NR^(a)C(O)NR^(a)(CH₂)_(r)—Q, (CH₂)_(r′)S(O)_(p)(CH₂)_(r)—Q,(CH₂)_(r′)SO₂NR^(a)(CH₂)_(r)—Q, (CH₂)_(r′)NR^(a)SO₂(CH₂)_(r)—Q, and(CH₂)_(r′)NR^(a)SO₂NR^(a)(CH₂)_(r)—Q;

Q is selected from H, a C₃₋₁₀ carbocyclic residue substituted with 0-5R^(c) and a 5-10 membered heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and S andsubstituted with 0-5 R^(c);

R² is selected from H, C₁₋₆ alkylene-H, C₂₋₆ alkenylene-H, C₂₋₆alkynylene-H, (CH₂)_(r′)O(CH₂)_(r)—H, (CH₂)_(r′)NR^(a)(CH₂)_(r)—H,(CH₂)_(r′)C(O) (CH₂)_(r)—H, (CH₂)_(r′)C(O)NR^(a)(CH₂)_(r)—H,(CH₂)_(r′)NR^(a)C(O)(CH₂)_(r)—H, (CH₂) _(r′)SO₂NR^(a)(CH₂)_(r)—H, and(CH₂)_(r′)NR^(a)SO₂(CH₂)_(r)—H;

U is absent or is selected from: O, NR^(a), C(O), C(O)NR^(a), andNR^(a)C(O);

X is absent or selected from C₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆alkynylene;

Y is absent or selected from O, NR^(a), C(O)NR^(a), and C(O), providedthat when U and Y are present, X is present;

Z is absent or selected from a C₃₋₁₀ carbocyclic residue substitutedwith 0-5 R^(d) and a 5-10 membered heterocyclic system containing from1-4 heteroatoms selected from the group consisting of N, O, and S andsubstituted with 0-5 R^(d);

U^(a) is absent or is selected from: O, NR^(a), C(O), C(O)NR^(a), andNR^(a)C(O);

X^(a) is absent or selected from C₁₋₆ alkylene, C₂₋₆ alkenylene, andC₂₋₆ alkynylene;

Y^(a) is absent or selected from O, NR^(a), C(O)NR^(a), and C(O),provided that when U^(a) and Y^(a) are present, X^(a) is present;

X¹ is absent or selected from C₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆alkynylene;

Z^(a) is selected from H, a C₃₋₁₀ carbocyclic residue substituted with0-5 R^(d) and a 5-10 membered heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and S andsubstituted with 0-5 R^(d);

R⁴ is selected from H, Q′, C₁₋₅ alkylene-Q′, C₂₋₅ alkenylene-Q′, C₂₋₅alkynylene-Q′, (CRR′)_(r′)O(CRR′)_(r)—Q′,(CRR′)_(r′)NR^(a)(CRR′)_(r)—Q′, (CRR′)_(r′)NR^(a)C(O)(CRR′)_(r)—Q′,

(CRR′)_(r′)C(O)NR^(a)(CRR′)_(r)—Q′,(CRR′)_(r′)NR^(a)C(O)NR^(a)(CRR′)_(r)—Q′, (CRR′)_(r′)C(O)(CRR′)_(r)—Q′,(CRR′)_(r′)C(O)O(CRR′)_(r)—Q′, (CRR′)_(r′)S(O)_(p)(CRR′)_(r)—Q′, and(CRR′)_(r′)SO₂NR^(a)(CRR′)_(r)—Q′;

R^(4a) is selected from H, C₁₋₄ alkyl, —C₁₋₄ alkyl-phenyl, and phenyl;

alternatively, R⁴ and R^(4a), together with the carbon to which they areattached, combine to form a 3-6 membered carbocyclic ring substitutedwith 0-3 R^(b) or a 3-6 membered heterocyclic ring containing from 1-3heteroatoms selected from N, O, and S(O)_(p) and substituted with 0-3R^(b);

Q′ is selected from H, phenyl substituted with 0-3 R^(b) and a 5-6membered heteroaryl system containing from 1-4 heteroatoms selected fromthe group consisting of N, O, and S and substituted with 0-3 R^(b);

R^(b′) is selected from H, Q, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q,(CRR′)_(r′)O(CRR′)_(r)—Q, (CRR′)_(r′)NR^(a)(CRR′)_(r)—Q,(CRR′)_(r)C(O)(CRR′)_(r)—Q, (CRR′)_(r)C(O)O(CRR′) _(r)—Q,(CRR′)_(r)C(O)NR^(a)(CRR′)_(r)—Q, (CRR′)_(r′)NR^(a)C(O)(CRR′)_(r)—Q, and(CRR′)_(r′)NR^(a)C(O)NR^(a)(CRR′)_(r)—Q;

R^(c), at each occurrence, is independently selected from C₁₋₆ alkyl,OR^(a), Cl, F, Br, I, ═O, CN, NO₂, NR^(a)R^(a′), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a′), R^(a)NC(O)NR^(a)R^(a′), OC(O)NR^(a)R^(a′),R^(a)NC(O)O, S(O)₂NR^(a)R^(a′), NR^(a)S(O)₂R^(a″),NR^(a)S(O)₂NR^(a)R^(a′), OS(O)₂NR^(a)R^(a′), NR^(a)S(O)₂O,S(O)_(p)R^(a″), CF₃, CF₂CF₃, C₅₋₁₀ carbocyclic residue and a 5-10membered heterocyclic system containing from 1-4 heteroatoms selectedfrom the group consisting of N, O, and S;

R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl,OR^(a), Cl, F, Br, I, ═O, CN, NO₂, NR^(a)R^(a′), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a′), R^(a)NC(O)NR^(a)R^(a′), OC(O)NR^(a)R^(a′),R^(a)NC(O)O, S(O)₂NR^(a)R^(a′), NR^(a)S(O)₂R^(a″),NR^(a)S(O)₂NR^(a)R^(a′), OS(O)₂NR^(a)R^(a′), NR^(a)S(O)₂O,S(O)_(p)R^(a″), CF₃, CF₂CF₃, C₃₋₁₀ carbocyclic residue and a 5-10membered heterocyclic system containing from 1-4 heteroatoms selectedfrom the group consisting of N, O, and S;

r, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5; and,

r′, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5.

In a more preferred embodiment, the present invention providescompounds, wherein:

A is selected from —CO₂H, —CONHOH, —CONHOR⁵, and —N(OH)COR⁵;

Q is selected from H, a C₅₋₁₀ carbocyclic residue substituted with 0-5R^(c) and a ₅₋₁₀ membered heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and S andsubstituted with 0-5 R^(c);

R² is selected from H, CH₃, and CH₂CH₃;

U is absent;

X is absent or is C₁₋₃ alkylene;

Y is absent;

Z is absent or is selected from a C₆₋₁₀ aryl group substituted with 0-3R^(d) and a 5-10 membered heteroaryl group containing from 1-4heteroatoms selected from the group consisting of N, O, and S andsubstituted with 0-3 R^(d);

U^(a) is absent;

X^(a) is absent or selected from C₁₋₃ alkylene and C₂₋₃ alkenylene;

Y^(a) is absent or selected from O and NR^(a);

X¹ is absent or is C₁₋₃ alkylene;

Z^(a) is selected from H, a C₅₋₁₀ carbocyclic residue substituted with0-5 R^(d) and a 5-10 membered heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and S andsubstituted with 0-5 R^(d);

R⁴ is selected from H, C₁₋₅ alkylene-Q′, (CH₂)_(r′)O(CH₂)_(r)—Q′, and(CH₂) _(r′)NR^(a)(CH₂)_(r)—Q′;

R^(4a) is selected from H and C₁₋₄ alkyl;

alternatively, R⁴ and R^(4a), together with the carbon to which they areattached, combine to form a 3-6 membered carbocyclic ring substitutedwith 0-3 R^(b);

Q′ is H or phenyl substituted with 0-3 R^(b);

R^(b′) is selected from H, C₁₋₄ alkylene-Q, C₂₋₄ alkenylene-Q,(CRR′)_(r′)O(CRR′)_(r)—Q, (CRR′)_(r′)NR^(a)(CRR′)_(r)—Q,(CRR′)^(r)C(O)(CRR′)_(r)—Q, (CRR′)_(r)C(O)NR^(a)(CRR′) _(r)—Q,(CRR′)_(r′)NR^(a)C(O)(CRR′)_(r)—Q;

r, at each occurrence, is selected from 0, 1, 2, and 3; and,

r′, at each occurrence, is selected from 0, 1, 2, and 3.

In an even more preferred embodiment, the present invention providescompounds, wherein:

A is selected from —CO₂H, —CONHOH, and —CONHOR⁵;

R¹ is selected from H, C₁₋₆ alkylene-Q, (CH₂)_(r′)O(CH₂)_(r)—Q,(CH₂)_(r′)NR^(a)(CH₂)_(r)—Q, (CH₂)_(r′)C(O)(CH₂)_(r)—Q,(CRR′)_(r′)C(O)O(CRR′)_(r)—Q, (CH₂)_(r′)C(O)NR^(a)(CH₂)_(r)—Q, and(CH₂)_(r′)NR^(a)C(O)(CH₂)_(r)—Q;

Q is selected from H, a C₅₋₁₀ carbocyclic residue substituted with 0-3R^(c) and a 5-10 membered heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and S andsubstituted with 0-5 R^(c);

R² is H;

X is absent or is CH₂ or CH₂CH₂;

Z is absent or is selected from phenyl substituted with 0-3 R^(d) and a5-6 membered heteroaryl group containing from 1-4 heteroatoms selectedfrom the group consisting of N, O, and S and substituted with 0-3 R^(d);

X^(a) is absent or is CH₂ or CH₂CH₂;

Y^(a) is absent or O;

X¹ is absent or is CH₂ or CH₂CH₂;

Z^(a) is selected from H, a C₅₋₁₀ carbocyclic residue substituted with0-5 R^(d) and a 5-10 membered heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and S andsubstituted with 0-5 R^(d);

R⁴ is selected from H, OH, NH₂, CH₃, CH₂OH, and CH₂NH₂;

R^(4a) is selected from H, CH₃ and CH₂CH₃;

alternatively, R⁴ and R^(4a), together with the carbon to which they areattached, combine to form a 3-5 membered carbocyclic ring substitutedwith 0-2 R^(b);

R^(b′) is selected from H, C₁₋₂ alkyl-Q, (CRR′)_(r′)NHR^(a), and(CRR′)_(r)C(O)NHR^(a);

R^(c), at each occurrence, is independently selected from C₁₋₆ alkyl,OR^(a), Cl, F, Br, I, ═O, CN, NO₂, NR^(a)R^(a′), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a′), R^(a)NC(O)NR^(a)R^(a′), OC(O)NR^(a)R^(a′),R^(a)NC(O)O, S(O)₂NR^(a)R^(a′), NR^(a)S(O)₂R^(a″),NR^(a)S(O)₂NR^(a)R^(a′), OS(O)₂NR^(a)R^(a′), NR^(a)S(O)₂O,S(O)_(p)R^(a″), CF₃, CF₂CF₃, C₅₋₆ carbocyclic residue and a 5-6 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S;

R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl,OR^(a), Cl, F, Br, I, ═O, CN, NO₂, NR^(a)R^(a′), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a′), R^(a)NC(O)NR^(a)R^(a′), OC(O)NR^(a)R^(a′),R^(a)NC(O)O, S(O)₂NR^(a)R^(a′), NR^(a)S(O)₂R^(a″), NR^(a)S(O)₂NR^(a)R^(a′), OS(O)₂NR^(a)R^(a′), NR^(a)S(O)₂O, S(O)_(p)R^(a″), CF₃,CF₂CF₃, C₃₋₆ carbocyclic residue and a 5-6 membered heterocyclic systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S; and,

r, at each occurrence, is selected from 0, 1, and 2;

r′, at each occurrence, is selected from 1, and 2; and,

s, at each occurrence, is selected from 0 and 1.

In a further preferred embodiment, the present invention provides novelcompounds of formula Ia, wherein:

In a further preferred embodiment, the present invention provides novelcompounds of formula Ib, wherein:

and n is selected from 1, 2, and 3.

In another preferred embodiment, the present invention provides novelcompounds is selected from:

(R)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-1-(4-methylphenyl)cyclopropanecarboxamide;

(R)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-1-(4-methoxyphenyl)cyclopropanecarboxamide;

(R)-N-[1-[(hydroxyamino)carbonyl]-3-(methylthio)propyl]-1-(4-methoxyphenyl)cyclopropanecarboxamide;

(R)-N-[1-[(hydroxyamino)carbonyl]-3-(methylsulfonyl)propyl]-1-(4-methoxyphenyl)cyclopropanecarboxamide;

N-[1-(R)-[(hydroxyamino)carbonyl]-2-methylpropyl]-N,α,α-trimethylbenzeneacetamide;

(R)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methyl-1-phenylcyclopropanecarboxamide;

(R)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methyl-1-(4-methylphenyl)cyclopropanecarboxamide;

(R)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-1-(4-methoxyphenyl)-N-methylcyclopropanecarboxamide;

(R)-1-(4-chlorophenyl)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methylcyclopropanecarboxamide;

(R)-1-(2,4-dichlorophenyl)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methylcyclopropanecarboxamide;

(R)-1-(4-chlorophenyl)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methylcyclobutanecarboxamide;

(R)-1-(4-chlorophenyl)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methylcyclopentanecarboxamide;

α-(R)-hydroxy-N-[1-(R)-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methylbenzeneacetamide;

1,1-dimethylethyl[2-[[1-(R)-[(hydroxyamino)carbonyl]-2-methylpropyl]methylamino]-2-oxo-1-phenylethyl]carbamate;

1-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-hydroxy-2-piperidinecarboxamide;

1-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-hydroxy-2-pyrrolidinecarboxamide;

(2R)-N-hydroxy-2-[[(4-methoxyphenyl)acetyl](methyl)amino]-3-methylbutanamide;

1-{4-[(2,4-dimethylbenzyl)oxy]phenyl}-N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methylcyclopropanecarboxamide;

(2S)-N-hydroxy-2-[[(4-methoxyphenyl)acetyl](methyl)amino]propanarmide;

N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methyl-1-[4-(2-naphthylmethoxy)phenyl]cyclopropanecarboxamide;

N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methyl-1-[4-(4-pyridinylmethoxy)phenyl]cyclopropanecarboxamide;

(2R)-2-[{[4-(benzyloxy)phenyl]acetyl}(methyl)amino]-N-hydroxy-3-methylbutanamide;

(2R)-2-[({4-[(3,5-dimethylbenzyl)oxy]phenyl}acetyl)(methyl)amino]-N-hydroxy-3-methylbutanamide;

(2R)-2-[{[4-(1H-1,2,3-benzotriazol-1-ylmethoxy)phenyl]acetyl}(methyl)amino]-N-hydroxy-3-methylbutanamide;

N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methyl-1-{4-[(3-phenyl-5-isoxazolyl)methoxy]phenyl}cyclopropanecarboxamide;

N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methyl-1-[4-(2-propynyloxy)phenyl]cyclopropanecarboxamide;

1-(4-{[3-(4-fluorophenyl)-5-isoxazolyl]methoxy}phenyl)-N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methylcyclopropanecarboxamide;

N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methyl-1-{4-[(3-propyl-5-isoxazolyl)methoxy]phenyl}cyclopropanecarboxamide;

N-{(1S)-1-[(hydroxyamino)carbonyl]-3-methylbutyl}-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-N-propylcyclopropanecarboxamide;

N-[3-(cyclopentylamino)propyl]-N-{(1S)-1-[(hydroxyamino)carbonyl]-3-methylbutyl}-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}cyclopropanecarboxamide;

tert-butyl (1S)-1-[4-(benzyloxy)phenyl]-2-[[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl](methyl)amino]-2-oxoethylcarbamate;

(1S)-N-hydroxy-2-([4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)pyrrolidinecarboxamide;

(1R)-N-hydroxy-2-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-pyrrolidinecarboxamide;

(3S)-N-hydroxy-2,2-dimethyl-4-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-3-thiomorpholinecarboxamide;

(2R)-N-hydroxy-1-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-2-piperidinecarboxamide;

tert-butyl3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-1-piperazinecarboxylate;

N-hydroxy-1-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-2-piperazinecarboxamide;

benzyl(3R)-3-[(hydroxyamino)carbonyl]-2-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)tetrahydro-1(2H)-pyridazinecarboxylate;

(3R)-N-hydroxy-2-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl)acetyl)hexahydro-3-pyridazinecarboxamide;

(3R)-N-hydroxy-2-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide;

2-((R/S)-2-phenylbutyramido)-N-hydroxy-(R)-propionamide;

2-((R/S)-α-Methyl-4-isobutylphenylacetamido)-N-hydroxy-(R)-propionamide;

2-((R/S)-2-Fluoro-α-methyl-4-biphenylacetamido)-N-hydroxy-(R)-propionarmide;

2-[N-Methyl-N-((R/S)-α-Methyl-4-benzyloxyphenylacetylamino)]-N-hydroxy-(R)-propionamide;

2-{N-Methyl-N-[(R/S)-α-methyl-4-(3,5-dimethylbenzyloxy)phenylacetyl]amino}-N-hydroxy-(R)-propionamide;

2-{N-Methyl-N-[(R/S)-α-methyl-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-N-hydroxy-(R)-propionamide;

2-{N-Methyl-N-[(R/S)-α-(methylaminocarbonylmethyl)-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-N-hydroxy-(R)-propionamide;

2-{N-Methyl-N-[(R/S)-α-(aminocarbonylmethyl)-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-N-hydroxy-(R)-propionamide;

2-{N-Methyl-N-[(R/S)-α-(1-piperazinocarbonylmethyl)-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-N-hydroxy-(R)-propionamide;

(2R)-2-[(amino{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)amino]-N-hydroxy-4-methylpentanamide;and,

2-[(amino{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)amino]-N-hydroxy-2-methylpropanamide

or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novelpharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method fortreating or preventing an inflammatory disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt form thereof.

In another embodiment, the present invention provides a novel method oftreating a condition or disease mediated by MMPs, TNF, aggrecanase, or acombination thereof in a mammal, comprising: administering to the mammalin need of such treatment a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt formthereof.

In another embodiment, the present invention provides a novel method oftreating a condition or disease wherein the disease or condition isreferred to as rheumatoid arthritis, osteoarthritis, periodontitis,gingivitis, corneal ulceration, solid tumor growth and tumor invasion bysecondary metastases, neovascular glaucoma, multiple sclerosis, orpsoriasis in a mammal, comprising: administering to the mammal in needof such treatment a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method oftreating a condition or disease wherein the disease or condition isreferred to as fever, cardiovascular effects, hemorrhage, coagulation,cachexia, anorexia, alcoholism, acute phase response, acute infection,shock, graft versus host reaction, autoimmune disease or HIV infectionin a mammal comprising administering to the mammal in need of suchtreatment a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides novel compounds offormula (I) for use in therapy.

In another embodiment, the present invention provides the use of novelcompounds of formula (I) for the manufacture of a medicament for thetreatment of a condition or disease mediated by MMPs, TNF, aggrecanase,or a combination thereof.

Definitions

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

When any variable (e.g., R^(b)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R⁶, then saidgroup may optionally be substituted with up to two R⁶ groups and R⁶ ateach occurrence is selected independently from the definition of R⁶.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “alkyl” or “alkylene” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. C₁₋₁₀ alkyl (or alkylene),is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkylgroups. Examples of alkyl include, but are not limited to, methyl,ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, ands-pentyl. “Haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogen(for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through an oxygen bridge. C₁₋₁₀ alkoxy, isintended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkoxygroups. Examples of alkoxy include, but are not limited to, methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy,and s-pentoxy. “Cycloalkyl” is intended to include saturated ringgroups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C₃₋₇cycloalkyl, is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. “Alkenyl” or “alkenylene” is intended to include hydrocarbonchains of either a straight or branched configuration and one or moreunsaturated carbon-carbon bonds which may occur in any stable pointalong the chain, such as ethenyl and propenyl. C₂₋₁₀ alkenyl (oralkenylene), is intended to include C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, andC₁₀ alkenyl groups. “Alkynyl” or “alkynylene” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more triple carbon-carbon bonds which may occur in any stablepoint along the chain, such as ethynyl and propynyl. C₂₋₁₀ alkynyl (oralkynylene), is intended to include C₂, C₃, C₄, C₅, C₆, C₇, Cs, C₉, andC₁₀ alkynyl groups.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which maybe saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane,[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,and tetrahydronaphthyl.

As used herein, the term “heterocycle” or “heterocyclic system” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, NH, O and S and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The nitrogen and sulfur heteroatoms may optionally beoxidized. The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. A nitrogen in theheterocycle may optionally be quaternized. It is preferred that when thetotal number of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1. Asused herein, the term “aromatic heterocyclic system” or “heteroaryl” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring whichconsists of carbon atoms and 1, 2, 3, or 4 heterotams independentlyselected from the group consisting of N, NH, O and S. It is to be notedthat total number of S and O atoms in the aromatic heterocycle is notmore than 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl. Also included are fused ring and spiro compounds containing,for example, the above heterocycles.

The term “amino acid” as used herein means an organic compoundcontaining both a basic amino group and an acidic carboxyl group.Included within this term are natural amino acids (e.g., L-amino acids),modified and unusual amino acids (e.g., D-amino acids), as well as aminoacids which are known to occur biologically in free or combined form butusually do not occur in proteins. Included within this term are modifiedand unusual amino acids,such as those disclosed in, for example, Robertsand Vellaccio (1983) The Peptides, 5: 342-429, the teaching of which ishereby incorporated by reference. Natural protein occurring amino acidsinclude, but are not limited to, alanine, arginine, asparagine, asparticacid, cysteine, glutamic acid, glutamine, glycine, histidine,isoleucine, leucine, lysine, methionine, phenylalanine, serine,threonine, tyrosine, tyrosine, tryptophan, proline, and valine. Naturalnon-protein amino acids include, but are not limited to arginosuccinicacid, citrulline, cysteine sulfinic acid, 3,4-dihydroxyphenylalanine,homocysteine, homoserine, ornithine, 3-monoiodotyrosine,3,5-diiodotryosine, 3,5,5′-triiodothyronine, and 3,3′,5,5′-tetraiodothyronine. Modified or unusual amino acids which can beused to practice the invention include, but are not limited to, D-aminoacids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid,2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyricacid, naphthylalanine, phenylglycine, β-phenylproline, tert-leucine,4-aminocyclohexylalanine, N-methyl-norleucine, 3,4-dehydroproline,N,N-dimethylaminoglycine, N-methylaminoglycine,4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid,trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid,1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fuimaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing,etc...) the compounds of the present invention may be delivered inprodrug form. Thus, the present invention is intended to cover prodrugsof the presently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers which release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention or an amount of the combination ofcompounds claimed effective to inhibit a MMP, TNF, aggrecanase, or acombination thereof in a host. The combination of compounds ispreferably a synergistic combination. Synergy, as described for exampleby Chou and Talalay, Adv. Enzyme Regul 1984, 22, 27-55, occurs when theeffect (in this case, inhibition of a desired target) of the compoundswhen administered in combination is greater than the additive effect ofthe compounds when administered alone as a single agent. In general, asynergistic effect is most clearly demonstrated at suboptimalconcentrations of the compounds. Synergy can be in terms of lowercytotoxicity, increased antiviral effect, or some other beneficialeffect of the combination compared with the individual components.

Synthesis

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents which are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

A series of acetamides of formula 6 are prepared by the method outlinedin Scheme 1. Reaction of BOC-protected D-amino acid 1 withO-benzylhydroxylamine and acid hydrolysis gives amine 3. Coupling of 3with acid 4 followed by hydrogenolysis using palladium on barium sulfateas a catalyst provides the desired hydroxamic acid 6.

A series of cyclopropanecarboxamides and cyclobutanecarboxarmides offormula 15 are prepared by the method outlined in Scheme 2.Mono-alkylation of α-substituted methyl acetate 7 with ethylene bromideand 1,3-dibromopropane, followed by treatment with sodium hydride inDMSO provides cyclopropanecarboxylates and cyclobutanecarboxylates,respectively. Hydrolysis of 9 gives the corresponding acid 10. Thisprotocol allows the preparation of 10 with wide range of R³ group.

Many of the requisite D-amino acid methyl ester 11 are commerciallyavailable or are prepared from commercial material by simple protectinggroup manipulations. Others are synthesized using Myers method fromglycine (Myers, A. G.; Gleason, J. L.; Yoon, T. J. Am. Chem. Soc. 1995,117, 8488), using Mitsunobu conditions from serine (Cherney, R. J.;Wang, L. J. Org. Chem. 1996, 61, 2544), or using Evans electrophilicazidations from carboxylic acids (Evans, D. A.; Britton, T. C.; Ellman,J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 401 1).

Coupling of 10 and 11 with HATU provides 12. At this point, R^(b′) groupis introduced by alkylation with R^(b′)—X under basic conditions.Hydrolysis and coupling with hydroxylamine then complete the synthesis.This synthetic scheme is flexible and allows independent incorporationof various R¹, R^(b′) and R³ groups during the synthesis.

A series of phenylacetamides of formula 18 are prepared following thesequence outlined in Scheme 3. The starting point for the synthesis isbenzyloxyphenylacetamide 13, an intermediate from Scheme 2. Deprotectionof benzyl group and reaction with triflic anhydride provides triflate17. Palladium-mediated coupling of 17 under Stille or Suzuki conditionsprovides 18. Alternatively, 17 reacts with lower or higher-ordercuprates to give 18. Ester 18 is then converted to the correspondinghydroxamic acid under standard conditions.

Another series of phenylacetamides of formula 19 are prepared followingthe sequence outlined in Scheme 4. Alkylation of phenol 16 with R^(3′)—Xyields ester 19. 19 is then converted to the corresponding hydroxamicacid under standard conditions.

Another series of phenylacetamides of formula 22 are prepared followingthe sequence outlined in Scheme 5. Starting from 13 when R³ is(p-methoxyphenyl)methoxymethylphenyl group, DDQ oxidation removes thep-methoxybenzyl group. Alcohol 20 is then converted to bromide 21.Alkylation of 21 with R³′—OH yields 22. Ester 22 is converted to thecorresponding hydroxamic acid under standard conditions.

Another series of acetamides of formula 27 with an isoxazole substituentat the a position are prepared using common intermediate 13 followingthe sequence outlined in Scheme 6. After t-butyl ester hydrolysis, theresultant carboxylic acid 23 is converted to aldehyde 25 byhydroboration and Swern oxidation. Oxime formation, in situ oxidationand [3+2] dipolar cycloaddition with R³′-substituted acetylene providesisoxazole 27. 27 is converted to the corresponding hydroxamic acid understandard conditions.

Another series of acetamides of formula 30 with an isoxazole substituentat the a position are prepared using common intermediate 13 followingthe sequence outlined in Scheme 7. Removal of trimethylsilyl group withNaOH gives terminal acetylene 28. Cycloaddition of 28 with oxime 29under oxidative conditions provides isoxazole 30. 30 is converted to thecorresponding hydroxamic acid under standard conditions.

Another series of acetamides of formula 34 with an azaoxazolesubstituent at the α position are prepared using common intermediate 22following the sequence outlined in Scheme 8. Acid 22 is first coupledwith hydrazine to give 31. Condensation with aldehyde 32 and oxidativecyclization with PhI(OAc)₂ providesb azaoxazole 34 (Yang, R. Y.; Dai, L.X. J. Org. Chem. 1993, 58, 3381). 34 is converted to the correspondinghydroxamic acid under standard conditions.

Another series of acetamides of formula 39 with an aminothiazolesubstituent at the α position are prepared following the sequenceoutlined in Scheme 9. Partial hydrogenation of acetylene 28 gives olefin35. 35 is converted to bromoketone 37 by Wacker oxidation andα-bromonation. Treatment of bromoketone 37 with thiourea producesaminothiazole 38 (Markees, D. G.; Burger, A. J. Am. Chem. Soc. 1948, 70,3329.), which is then alkylated with R^(3′)—X. Ester 39 is converted tothe corresponding hydroxamic acid under standard conditions.

Employing the synthetic sequence described as before, a series ofacetamides of formula 42 with an imidazole substituent at the a positionare prepared from intermediate 41 (Scheme 10). Likewise, through anintermediacy of 44, ester 43 is converted to a series ofthiophene-substituted acetamides 45.

One diasteriomer of a compound of Formula I may display superioractivity compared with the others. Thus, the following stereochemistriesare considered to be a part of the present invention.

When required, separation of the racemic material can be achieved byHPLC using a chiral column or by a resolution using a resolving agentsuch as camphonic chloride as in Steven D. Young, et al, AntimicrobialAgents and Chemotheraphy 1995, 2602-2605. A chiral compound of Formula Imay also be directly synthesized using a chiral catalyst or a chiralligand, e.g., Andrew S. Thompson, et al, Tet. lett. 1995, 36,8937-8940).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

Abbreviations used in the Examples are defined as follows: “1×” foronce, “2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq”for equivalent or equivalents, “g” for gram or grams, “mg” for milligramor milligrams, “mL” for milliliter or milliliters, “¹H” for proton, “h”for hour or hours, “M” for molar, “min” for minute or minutes, “MHz” formegahertz, “MS” for mass spectroscopy, “NMR” for nuclear magneticresonance spectroscopy, “rt” for room temperature, “tlc” for thin layerchromatography, “v/v” for volume to volume ratio. “α”, “β”, “R” and “S”are stereochemical designations familiar to those skilled in the art.

Example 1(R)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-1-(4-methylphenyl)cyclopropanecarboxamide

(1a) BOP reagent (20.35 g, 1 eq) was added to a mixture N-t-BOC-D-valine(10.0 g, 46.0 mmol), O-benzyl hydroxylamine hydrochloride (14.69 g, 2eq), N,N-diisopropylethylamine (32.9 mL, 4 eq) and N,N-dimethylformamide(50 mL) at 0° C. After 10 min at 0° C. and 3 h at rt, ethyl acetate (400mL) was added. The mixture was washed successively with 10% citric acid(2×60 mL), saturated brine (2×60 mL), saturated sodium bicarbonate (60mL), brine (60 mL), dried (MgSO₄) and concentrated. The desired productwas collected by crystallization from ethyl acetate-hexane (1:1) as awhite solid (11.0 g, 74%). MS found: (M+H)⁺=323.

(1b) The amide (11.0 g, 34.0 mmol) from reaction (1a) was stirred in 4.0M dioxane solution of hydrogen chloride (85 mL) at rt for 1 h. Removalof solvent in vacuo provided crude amine hydrochloride (10.55 g). Thismaterial was used in the next step without purification.

(1c) N,N-diisopropylethylamine (0.539 mL, 4 eq) was added to a mixtureof the crude amine hydrochloride (200 mg) from reaction (1b),1-(4-methylphenyl)-1-cyclopropane carboxylic acid (163 mg, 1.2 eq) andHATU (441 mg, 1.5 eq) in N,N-dimethylformamide (1 mL). The mixture wasstirred at room temperature overnight and at 70° C. for 90 min.Following addition of ethyl acetate (100 mL), the mixture was washedwith 1:1 mixture of 1 N hydrochloric acid-saturated brine (2×10 mL),dried (MgSO₄) and concentrated. Silica gel column chromatography (ethylacetate-hexane, 40:60) yielded the desired product (127 mg, 52% for twosteps). MS found: (M+H)⁺=381.

(1d) A mixture of the O-benzylhydroxamic acid (115 mg, 0.303 mmol) fromreaction (1c) and 5% palladium on barium sulfate (0.46 g) in methanol (5mL) was stirred under balloon pressure hydrogen for 90 min. The catalystwas removed by filtration and the filtrate was concentrated to give thedesired hydroxamic acid (90.3 mg, 100%). MS found: (M−H)⁻=289.

Example 2(R)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-1-(4-methoxyphenyl)cyclopropanecarboxamide

(2a) In a procedure analogous to that described for reaction (1c), thecrude amine hydrochloride (200 mg) from reaction (1b) was reacted with1-(4-methoxyphenyl)-1-cyclopropane carboxylic acid (178 mg, 1.2 eq) togive the desired O-benzylhydroxamic acid (107 mg, 42% for two steps). MSfound: (M+Na)⁺=419.

(2b) In a procedure analogous to that described for reaction (1d), theO-benzylhydroxamic acid (90.0 mg, 0.223 mmol) from reaction (2a) washydrogenolyzed to give the desired hydroxamic acid (69.7 mg, 100%). MSfound: (M−H)⁻=305.

Example 3(R)-N-[1-[(hydroxyamino)carbonyl]-3-(methylthio)propyl]-1-(4-methoxyphenyl)cyclopropanecarboxamide

(3a) In a procedure analogous to that described for reaction (1c),D-methionine methyl ester hydrochloride (2.00 mg, 10.0 mmol) was reactedwith 1-(4-methoxyphenyl)-1-cyclopropane carboxylic acid (2.31 g, 1.2 eq)to give the desired amide (3.17 g, 94%). MS found: (M+H)⁺=338.

(3b) Preparation of hydroxylamine/potassium hydroxide solution: Asolution of potassium hydroxide (2.81 g, 1.5 eq) in methanol (7 mL) wasadded to a hot solution of hydroxylamine hydrochloride (2.34 g, 33.7mmol) in methanol (12 mL). After the mixture was cooled to roomtemperature, the precipitate was removed by filtration. The filtrate wasused fresh and assumed hydroxylamine concentration of 1.76 M.

The above freshly prepared 1.76 M hydroxylamine solution (0.74 mL, 4 eq)was added to the ester (110 mg, 0.326 mmol) from reaction (3a) inmethanol (2 mL). After 3 h at rt, the solution was adjusted to pH 4.0with 1 N HCl. After removal of methanol in vacuo, the residue wasextracted with ethyl acetate. The organic extracts were washed withbrine, dried (MgSO₄) and concentrated. Preparative thin layerchromatography (methanol-dichloromethane, 7.5:92.5) gave the desiredhydroxamic acid (55.2 mg, 50%). MS found: (M−H)⁻=337.

Example 4(R)-N-[1-[(hydroxyamino)carbonyl]-3-(methylsulfonyl)propyl]-1-(4-methoxyphenyl)cyclopropanecarboxamide

(4a) A solution of Oxone® (0.60 g) in water (2.6 mL) was added to thesulfide (220 mg, 0.650 mmol) from reaction (3a) in methanol (2.6 mL) at0° C. After 4 h at rt, the mixture was diluted with water and extractedwith chloroform three times. The combined extracts were washed withwater, brine, dried (Na₂SO₄) and concentrated to give the desiredsulfone (240 mg, 100%). MS found: (M+H)⁺=370.

(4b) In a procedure analogous to that described for reaction (3b), theester (157 mg, 0.425 mmol) from reaction (4a) was reacted withhydroxylamine to give the desired hydroxamic acid (140,4 mg, 89%). MSfound: (M−H)⁻=369.

Example 5N-[1-(R)-[(hydroxyamino)carbonyl]-2-methylpropyl]-N,alpha,alpha-trimethylbenzeneacetamide

(5a) In a procedure analogous to that described for reaction (1a),N-t-BOC-N-methyl-D-valine (5.00 g, 21.6 mmol) was reacted withO-benzylhydroxylamine hydrochloride (5.18 g, 1.5 eq). Silica gel columnchromatography (ethyl acetate-hexane, 25:75) yielded the desired amide(6.63 g, 91%). MS found: (M+H)⁺=337.

(5b) In a procedure analogous to that described for reaction (1b), theamide (144 mg, 1. eq) from reaction (5a) was reacted with hydrogenchloride to give the desired amine hydrochloride (5.49 g, 100%). MSfound: (M+H)⁺=237.

(5c) In a procedure analogous to that described for reaction (1c),α,α-dimethylphenylacetic acid (144 mg, 1.2 eq) was reacted with theamine (200 mg, 0.734 mmol) from reaction (5b). Silica gel columnchromatography (ether-dichloromethane-hexane, 25:25:50) yielded thedesired product (92.8 mg, 33%). MS found: (M−H)⁻=381.

(5d) In a procedure analogous to that described for reaction (1d), theO-benzylhydroxamic acid (78.7 mg, 0.206 mmol) from reaction (5c) washydrogenolyzed. Preparative thin layer chromatography(methanol-dichloromethane, 5:95) gave the desired hydroxamic acid (48mg, 80%). MS found: (M−H)⁻=291.

Example 6(R)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methyl-1-phenylcyclopropanecarboxamide

(6a) In a procedure analogous to that described for reaction (1c),1-phenyl-1-cyclopropane carboxylic acid (140 mg, 1.2 eq) was reactedwith the amine (200 mg, 0.734 mmol) from reaction (5b). Silica gelcolumn chromatography (ethyl acetate-hexane, 35:65) yielded the desiredproduct (64.2 mg, 26%). MS found: (M−H)⁻=379.

(6b) In a procedure analogous to that described for reaction (Id), theO-benzylhydroxamic acid (59.5 mg, 0.163 mmol) from reaction (6a) washydrogenolyzed to give the desired hydroxamic acid (43.8 mg, 93%). MSfound: (M−H)⁻=289.

Example 7(R)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methyl-1-(4-methylphenyl)cyclopropanecarboxamide

(7a) In a procedure analogous to that described for reaction (1c),1-(4-methylphenyl)-1-cyclopropane carboxylic acid (155 mg, 1.2 eq) wasreacted with the amine (200 mg, 0.734 mmol) from reaction (5b). Silicagel column chromatography (ethyl acetate-hexane, 35:65) yielded thedesired product (118.4 mg, 41%). MS found: (M+Na)⁺=417.

(7b) In a procedure analogous to that described for reaction (1d), theO-benzylhydroxamic acid (110 mg, 0.279 mmol) from reaction (7a) washydrogenolyzed to give the desired hydroxamic acid (84.2 mg, 99%). MSfound: (M−H)⁻=303.

Example 8(R)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-1-(4-methoxyphenyl)-N-methylcyclopropanecarboxamide

(8a) In a procedure analogous to that described for reaction (1c),1-(4-methoxyphenyl)-1-cyclopropane carboxylic acid (169 mg, 1.2 eq) wasreacted with the amine (200 mg, 0.734 mmol) from reaction (5b). Silicagel column chromatography (ethyl acetate-hexane, 35:65) yielded thedesired product (158 mg, 52%). MS found: (M+H)⁺=411.

(8b) In a procedure analogous to that described for reaction (1d), theO-benzylhydroxamic acid (150 mg, 0.365 mmol) from reaction (8a) washydrogenolyzed. Preparative thin layer chromatography(methanol-dichloromethane, 7:93) gave the desired hydroxamic acid (52.2mg, 45%). MS found: (M−H)⁻=319.

Example 9(R)-1-(4-chlorophenyl)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methylcyclopropanecarboxamide

(9a) In a procedure analogous to that described for reaction (1c),1-(4-chlorophenyl)-1-cyclopropane carboxylic acid (150 mg, 0.763 mmol)was reacted with the amine (312 mg, 1.2 eq) from reaction (5b). Silicagel column chromatography (ethyl acetate-hexane, 30:70 then 40:60)yielded the desired product (188.8 mg, 60%). MS found: (M−H)⁻=413.

(9b) In a procedure analogous to that described for reaction (1d), theO-benzylhydroxamic acid (188.8 mg, 0.455 mmol) from reaction (9a) washydrogenolyzed to give the desired hydroxamic acid (142 mg, 96%). MSfound: (M−H)⁻=323.

Example 10(R)-1-(2,4-dichlorophenyl)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methylcyclopropanecarboxamide

(10a) In a procedure analogous to that described for reaction (1c),1-(2,4-dichlorophenyl)-1-cyclopropane carboxylic acid (406 mg, 1.2 eq)was reacted with the amine (400 mg, 1.46 mmol) from reaction (5b).Silica gel column chromatography (ethyl acetate-hexane, 35:65) yieldedthe desired product (180 mg, 27%). MS found: (M+Na)⁺=471.

(10b) In a procedure analogous to that described for reaction (1d), theO-benzylhydroxamic acid (180 mg, 0.401 mmol) from reaction (10a) washydrogenolyzed to give the desired hydroxamic acid (113 mg, 79%). MSfound: (M−H)⁻=357.

Example 11(R)-1-(4-chlorophenyl)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methylcyclobutanecarboxamide

(11a) In a procedure analogous to that described for reaction (1c),1-(4-chlorophenyl)-1-cyclobutane carboxylic acid (371 mg, 1.2 eq) wasreacted with the amine (400 mg, 1.46 mmol) from reaction (5b). Silicagel column chromatography (ethyl acetate-hexane, 30:70) yielded thedesired product (340 mg, 54%). MS found: (M+H)⁺=429.

(11b) In a procedure analogous to that described for reaction (1d), theO-benzylhydroxamic acid (300 mg, 0.700 mmol) from reaction (11a) washydrogenolyzed to give the desired hydroxamic acid (187 mg, 79%). MSfound: (M−H)⁻=337.

Example 12(R)-1-(4-chlorophenyl)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methylcyclopentanecarboxamide

(12a) In a procedure analogous to that described for reaction (1c),1-phenyl-1-cyclopentane carboxylic acid (144 mg, 0.755 mmol) was reactedwith the amine (309 mg, 1.5 eq) from reaction (5S) at 60° C. for 60 h.Silica gel column chromatography (ethyl acetate-hexane, 15:85 then25:75) yielded the desired product (78.4 mg, 25%). MS found: (M−H)⁻=407.

(12b) In a procedure analogous to that described for reaction (1d), theO-benzylhydroxamic acid (78.4 mg, 0.192 mmol) from reaction (12a) washydrogenolyzed to give the desired hydroxamic acid (43.7 mg, 72%). MSfound: (M−H)⁻=317.

Example 13alpha-(R)-hydroxy-N-[1-(R)-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methylbenzeneacetamide

(13a) In a procedure analogous to that described for reaction (1c),(+)-mandelic acid (134 mg, 1.2 eq) was reacted with the amine (200 mg,0.734 mmol) from reaction (5b) at rt for 4 h. Silica gel columnchromatography (ethyl acetate-hexane, 50:50) yielded the desired product(106 mg, 39%). MS found: (M+H)⁺=371.

(13b) In a procedure analogous to that described for reaction (1d), theO-benzylhydroxamic acid (84.2 mg, 0.301 mmol) from reaction (13a) washydrogenolyzed. Preparative thin layer chromatography(methanol-chloroform, 20:80) gave the desired hydroxamic acid (31.1 mg,37%). MS found: (M−H)⁻=279.

Example 141,1-dimethylethyl[2-[[1-(R)-[(hydroxyamino)carbonyl]-2-methylpropyl]methylamino]-2-oxo-1-phenylethyl]carbamate

(14a) In a procedure analogous to that described for reaction (1c),N-BOC-L-phenylglycine (220 mg, 1.2 eq) was reacted with the amine (200mg, 0.734 mmol) from reaction (5b) at rt overnight. Silica gel columnchromatography (ethyl acetate-hexane, 35:65) yielded the desired product(240 mg, 70%) as a 3:1 mixture of two diastereomers due to partialepimerization of the phenylglycine section. MS found: (M+H)⁺=470.

(14b) In a procedure analogous to that described for reaction (1d), theO-benzylhydroxamic acid (100 mg, 0.322 mmol) from reaction (14a) washydrogenolyzed to give the desired hydroxamic acid (87.7 mg, 100%). MSfound: (M+H)⁺=380.

Examples 15-31 can be made analogously to Examples 1 -14, utilizingnecessary modifications obvious to one skilled in the art.

Example 151-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-hydroxy-2-piperidinecarboxamideExample 161-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-hydroxy-2-pyrrolidinecarboxamideExample 17(2R)-N-hydroxy-2-[[(4-methoxyphenyl)acetyl](methyl)amino]-3-methylbutanamideExample 181-{4-[(2,4-dimethylbenzyl)oxylpheny]}-N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methylcyclopropanecarboxamideExample 19(2S)-N-hydroxy-2-[[(4-methoxyphenyl)acetyl](methyl)amino]propanamideExample 20N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methyl-1-[4-(2-naphthylmethoxy)phenyl]cyclopropanecarboxamideExample 21N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methyl-1-[4-(4-pyridinylmethoxy)phenyl]cyclopropanecarboxamidetrifluoroacetic acid salt Example 22(2R)-2-[{[4-(benzyloxy)phenyl]acetyl}(methyl)amino]-N-hydroxy-3-methylbutanamideExample 23(2R)-2-[({4-[(3,5-dimethylbenzyl)oxylphenyl]acetyl)(methyl)amino]-N-hydroxy-3-methylbutanamideExample 24(2R)-2-[{[4-(1H-1,2,3-benzotriazol-1-ylmethoxy)phenyl]acetyl}(methyl)amino]-N-hydroxy-3-methylbutanamideExample 25N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methyl-1-{4-[(3-phenyl-5-isoxazolyl)methoxy]phenyl}cyclopropanecarboxamideExample 26N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methyl-1-[4-(2-propynyloxy)phenyl]cyclopropanecarboxamideExample 271-(4-{[3-(4-fluorophenyl)-5-isoxazolyl]methoxy}phenyl)-N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methylcyclopropanecarboxamideExample 28N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methyl-1-{4-[(3-propyl-5-isoxazolyl)methoxy]phenyl}cyclopropanecarboxamideExample 29N-{(1S)-1-[(hydroxyamino)carbonyl]-3-methylbutyl}-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-N-propylcyclopropanecarboxamidetrifluoroacetic acid salt Example 30N-[3-(cyclopentylamino)propyl]-N-{(1S)-1-[(hydroxyamino)carbonyl]-3-methylbutyl}-1-{4-[(2-methyl-4-guinolinyl)methoxy]phenyl}cyclopropanecarboxamidebis-trifluoroacetic acid salt Example 31 tert-butyl(1S)-1-[4-(benzyloxy)phenyl]-2-[[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl](methyl)amino]-2-oxoethylcarbamateExample 322-[4-(benzyloxy)phenyl]-N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-2-pyrrolidinecarboxamidetrifluoroacetic acid salt

(32a) To a stirred, cooled (−78° C. ) solution of 0.35 grams of methyl{[(benzyloxy)carbonyl]amino}[4-(benzyloxy)phenyl]acetate in 10 mL oftetrahydrofuran and 1 mL of DMPU was added 2.03 mL of 1M LDA followedafter 1 hour with the addition of 0.102 mL of 1-bromo-2-propane. Thereaction was allowed to slowly warm to room temperature, quenched withsaturated aqueous citric acid and extracted 3 times with ethyl acetate.The combined organics were washed with water, brine, dried over MgSO₄and the volatiles were removed under reduced pressure affording thetitle material. LRMS found (M+Na)⁺=434.

(32b) To 0.1 grams of material from example 32a in 2.5 mL of methanol,1.5 mL of dimethyl sulfoxide and 1 mL of water was added 0.1 grams oflithium hydroxide and heated at 78° C. overnight. The volatiles wereremoved under reduced pressure and the remaining material was dilutedwith ether washed with 1N HCl and extracted 3 times with ether. Thecombined ether extracts were washed with brine, dried over MgSO₄ and thevolatiles were removed under reduced pressure affording the titlecompound. LRMS found (M+H)⁺=398.

(32c) To the material from example 32b in 0.5 mL of dimethylformamidewas added 0.13 mL of N-methylmorpholine, 0.084 grams of HATU and 0.083grams of D-leucine methylester hydrochloride. After stirring one hour atroom temperature the reaction was heated at 80° C. for an additionalhour. The mixture was diluted with ethyl acetate and washed with 1N HCl.The aqueous was extracted an additional three times with ethyl acetate.The combined extracts were washed with brine, saturated aqueous sodiumbicarbonate, brine, dried over MgSO₄ and the volatiles were removedunder reduced pressure affording the title material as a mixture ofdiastereomers. The isomers were separated by silica gel chromatographyeluting with a gradient of 10-25% ethyl acetate/hexane affording thetitle compounds. LRMS for both found (M+H)⁺=525.

(32d) To 0.035 grams of the faster diastereomer from example 32c in 0.5mL tetrahydrofuran and 0.5 mL of water was added 0.014 grams of lithiumhydroxide monohydrate. After stirring at ambient temperature for 2 hoursthe reaction was acidified with 1N HCl which had been previouslysaturated with sodium chloride. The mixture was extracted three timeswith ethyl acetate. The extracts were washed with brine, dried overMgSO₄ and the volatiles were removed under reduced pressure affordingthe title compound. LRMS found (M+H)⁺=511.

(32e) To 0.029 grams of compound from example 32d in 1 mL ofdimethylformamide was added 0.062 mL of N-methylmorpholine, 0.020 gramsof hydroxylamine hydrochloride, and 0.033 grams of BOP. After stirringat ambient temperature overnight the reaction was diluted with a mixtureof 1N HCl, water and brine, then extracted 3 times with ethyl acetate.The combined extracts were washed with brine, saturated aqueous sodiumbicarbonate, brine, dried over MgSO₄ and the volatiles were removedunder reduced pressure. The resulting material was purified by reversephase C-18 HPLC affording the title compound. LRMS found (M+H)⁺=526.

(32f) To 0.011 grams of material from example 32e in 1 mL ofdichloromethane was added 0.1 mL of trifluoroacetic acid. After stirringfor 1 hour at ambient temperature the volatiles were removed underreduced pressure affording the title compound. LRMS found (M+H)⁺=426.

Example 33(1S)-N-hydroxy-2-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)pyrrolidinecarboxamidetrifluoroacetic acid salt

(33a) To 3.0 grams of methyl (4-hydroxyphenyl)acetate in 200 mL ofacetone was added 2.74 grams of sodium iodide, 4.59 grams of4-(chloromethyl)-2-methylquinoline and 25 grams of potassium carbonate.After heating the mixture at 55° C. overnight it was concentrated ˜80%under reduced pressure. The resulting material was diluted with etherand water and separated. The aqueous was extracted an additional twotimes with ether. The combined ether extracts were then extracted twicewith 1N HCl. The acidic aqueous were combined and washed once withether. The aqueous was then rendered basic with the addition ofsaturated aqueous sodium bicarbonate and extracted three times withethyl acetate. The ethyl acetate extracts were combined, dried overMgSO₄ and the volatiles were removed under reduced pressure. Theresulting material was chromatographed on silica gel eluting with agradient of 25 to 80% ethyl acetate/hexane affording the title compound.LRMS found (M+H)⁺=322.

(33b) To 4.0 grams of the compound from 34a in 50 mL of tetrahydrofuranand 50 mL of water was added 1.05 grams of lithium hydroxidemonohydrate. After stirring 30 minutes at ambient temperature themixture was poured into saturated aqueous ammonium chloride andextracted three times with ethyl acetate. The combined organic extractswere washed with brine, dried over magnesium sulfate and the volatileswere removed under reduced pressure affording 1 gram of the titlematerial. The original aqueous was acidified with 1N HCl and aprecipitate formed. This was not readily soluble in any of the solventstried, but the aqueous was extracted with chloroform, ethyl acetate andbenzene. All of the organic extracts were combined, washed with brine,dried over MgSO₄, and the volatiles were removed under reduced pressure.This afforded an additional 2 grams of the title material. LRMS found(M+H)⁺=308.

(33c) To 0.20 grams of the material from example 33b in 2 mL ofdimethylformamide was added 0.43 mL of N-methylmorpholine and 0.285grams of HATU. After stirring 5 minutes at ambient temperature 0.225grams of D-proline methylester was added. The reaction was stirred onehour at 80° C., poured into saturated aqueous ammonium chloride andextracted three times with ethylacetate. The combined organics werewashed with brine, saturated aqueous sodium bicarbonate, brine, driedover MgSO₄ and, passed through a short plug of silica gel eluting withethyl acetate. The volatiles were removed under reduced pressureaffording the title compound. LRMS found (M+H)⁺=419

(33d) To 0.190 grams of material from example 33c in 2 mL oftetrahydrofuran and 2 mL of water was added 0.095 grams of lithiumhydroxide monohydrate. The reaction was stirred 45 minutes at ambienttemperature, acidified by the addition of 2.25 mL of 1.00 M hydrochloricacid, extracted three times with ethylacetate, twice with benzene, andthree times with chloroform. All of the extracts were combined, driedover MgSO₄ and the volatiles were removed under reduced pressureaffording the title compound. LRMS found (M+H)⁺=405.

(33e) To 0.110 grains of material from example 33d in 2 mL ofdimethylformamide was added 0.21 mL of N-methylmorpholine, 0.095 gramsof hydroxylamine hydrochloride and 0.132 grams of BOP. After stirringfor 2 hours at ambient temperature the material was poured intosaturated aqueous sodium bicarbonate and extracted three times withethyl acetate. All the extracts were combined, dried over MgSO₄ and thevolatiles were removed under reduced pressure. The material wasdissolved in methanol/dimethylsulfoxide with 0.1 mL of trifluoroaceticacid and purified by reverse phase C-18 HPLC affording the titlematerial. LRMS found (M+H)⁺=420.

Example 34(1R)-N-hydroxy-2-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)pyrrolidinecarboxamidetrifluoroacetic acid salt

(34a) To 0.20 grams of the material from example 33b in 2 mL ofdimethylformamide was added 0.43 mL of N-methylmorpholine and 0.285grams of HATU. After stirring 5 minutes at ambient temperature 0.225grams of L-proline methylester was added. The reaction was stirred onehour at 80° C. and poured into 2.6 mL of 1.00 N HCl and extracted threetimes with ethylacetate. The combined organics were washed with brine,saturated aqueous sodium bicarbonate, brine, dried over MgSO₄ and,passed through a short plug of silica gel eluting with ethyl acetate.The volatiles were removed under reduced pressure affording the titlecompound. LRMS found (M+H)⁺=419.

(34b) To 0.110 grams of material from example 34a in 1.5 mL oftetrahydrofuran and 1.5 mL of water was added 0.056 grams of lithiumhydroxide monohydrate. The reaction was stirred 30 minutes at ambienttemperature, neutralized by the addition of 1.30 mL of 1.00 Mhydrochloric acid, extracted three times with ethyl acetate. All of theextracts were combined, dried over MgSO₄ and the volatiles were removedunder reduced pressure affording the title compound. LRMS found(M+H)⁺=405.

(34c) To 0.10 grams of material from example 33d in 1 mL ofdimethylformamide was added 0.19 mL of N-methylmorpholine, 0.086 gramsof hydroxylamine hydrochloride and 0.120 grams of BOP. After stirringfor 3 hours at ambient temperature the material was poured intosaturated aqueous sodium bicarbonate and extracted three times withethyl acetate. All the extracts were combined, dried over MgSO₄ and thevolatiles were removed under reduced pressure. The material was purifiedby reverse phase C-18 HPLC affording the title material. LRMS found(M+H)⁺=420.

Example 35(3S)-N-hydroxy-2,2-dimethyl-4-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-3-thiomorpholinecarboxamidetrifluoroacetic acid salt

(35a) To 0.20 grams of the material from example 33b in 2 mL ofdimethylformamide was added 0.21 mL of N-methylmorpholine and 0.285grams of HATU. After stirring 5 minutes at ambient temperature 0.301grams of tert-butyl (3S)-2,2-dimethyl-3-thiomorpholinecarboxylate wasadded. The reaction was stirred one hour at 80° C. and poured intosaturated aqueous ammonium chloride and extracted three times withethylacetate. The combined organics were washed with brine, saturatedaqueous sodium bicarbonate, brine, dried over MgSO₄, and the volatileswere removed under reduced pressure. The material was chromatographed onsilica gel eluting with a gradient of 20 to 50% ethyl acetate in hexanesaffording the title compound. LRMS found (M+H)⁺=521.

(35b) To 0.225 grams of material from example 35a was added 5 ml ofdichloromethane and 5 mL of trifluoroacetic acid. The reaction wasstirred 2 hours at ambient temperature and the volatiles were removedunder reduced pressure affording the title compound as the TFA salt.LRMS found (M+H)⁺=465.

(35c) To 0.220 grams of material from example 35b in 4 mL ofdimethylformamide was added 0.33 mL of N-methylmorpholine, 0.132 gramsof hydroxylamine hydrochloride and 0.185 grams of BOP. After stirringfor 3 hours at ambient temperature the material was poured intosaturated aqueous sodium bicarbonate and extracted three times withethyl acetate. All the extracts were combined, dried over MgSO₄ and thevolatiles were removed under reduced pressure. The material was purifiedby reverse phase C-18 HPLC affording the title material. LRMS found(M+H)⁺=480.3.

Example 36(2R)-N-hydroxy-1-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-2-piperidinecarboxamidetrifluoroacetic acid salt

(36a) To 0.20 grams of the material from example 33b in 2 mL ofdimethylformamide was added 0.43 mL of N-methylmorpholine and 0.285grams of HATU. After stirring 5 minutes at ambient temperature 0.234grams of methyl (2R)-2-piperidinecarboxylate was added. The reaction wasstirred for 30 minutes at ambient temperature and one hour at 80° C. Thereaction was poured into saturated aqueous ammonium chloride andextracted three times with ethylacetate. The combined organics werewashed with brine, saturated aqueous sodium bicarbonate, brine, driedover MgSO₄, and the volatiles were removed under reduced pressure. Thematerial was chromatographed on silica gel eluting with a gradient of 20to 40% ethyl acetate in hexanes affording the title compound. LRMS found(M+H)⁺=433.

(36b) To 0.235 grams of material from example 36a in 2 mL oftetrahydrofuran and 2 mL of water was added 0.109 grams of lithiumhydroxide monohydrate. The reaction was stirred 1 hour at ambienttemperature then 0.050 grams of lithium hydrate monohydrate was added.After stirring an additional hour the reaction was neutralized by theaddition of 4.0 mL of 1.00 M hydrochloric acid, extracted three timeswith ethylacetate. All of the extracts were combined, dried over MgSO₄and the volatiles were removed under reduced pressure affording thetitle compound. LRMS found (M+H)⁺=419.

(36c) To 0.175 grams of material from example 36b in 2 mL ofdimethylformamide was added 0.32 mL of N-methylmorpholine, 0.145 gramsof hydroxylamine hydrochloride and 0.204 grams of BOP. After stirringfor 4 hours at ambient temperature the material was poured intosaturated aqueous sodium bicarbonate and extracted three times withethyl acetate. All the extracts were combined, dried over MgSO₄ and thevolatiles were removed under reduced pressure. The material was purifiedby reverse phase C-18 HPLC followed by triteration with ether affordingthe title material. LRMS found (M+H)⁺=434.3.

Example 37 tert-butyl3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-1-piperazinecarboxylatetrifluoroacetic acid salt

(37a) To the 0.260 grams of material from example 33b in 5 mL of benzenewas added 0.31 mL of thionyl chloride. The reaction was heated at 55° C.for 2 hours. The volatiles were removed under reduced pressure affordingthe title compound as the HCl salt. LRMS found (M+H)⁺=322.

(37b) To 0.20 grams of material from example 37a in 5 mL ofdichloromethane was added 0.127 grams of the4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid and 0.183 mL ofN-methylmorpholine. After stirring the reaction for 2 hours at ambientthe volatiles were removed under reduced pressure and the resultingmaterial was chromatographed on C-18 reverse phase HPLC affording thetitle material as a TFA salt. LRMS found (M+H)⁺=520.4.

(37c) To 0.150 grams of material from example 37b in 4 mL ofdimethylformamide was added 0.21 mL of N-methylmorpholine, 0.126 gramsof hydroxylamine hydrochloride and 0.126 grams of BOP. After stirringfor 4 hours at ambient temperature the material was poured intosaturated aqueous sodium bicarbonate and extracted three times withethyl acetate. All the extracts were combined, dried over MgSO₄ and thevolatiles were removed under reduced pressure. The material was purifiedby reverse phase C-18 HPLC affording the title material as the TFA salt.LRMS found (M+H)⁺=535.

Example 38N-hydroxy-1-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-2-piperazinecarboxamnidebis-trifluoroacetic acid salt

(38a) To 0.010 grams of material from example 37c was added 0.5 ml ofdichloromethane and 0.55 mL of trifluoroacetic acid. The reaction wasstirred 2 hours at ambient temperature and the volatiles were removedunder reduced pressure affording the title compound as the bis TFA salt.LRMS found (M+H)⁺=435.

Example 39 benzyl(3R)-3-[(hydroxyamino)carbonyl]-2-(}4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)tetrahydro-1(2H)-pyridazinecarboxylatetrifluoroacetic acid salt

(39a) To 0.050 grams of 1-benzyl 3-methyl(3R)-tetrahydro-1,3(2H)-pyridazinedicarboxylate in 1 mL ofdichloroethane was added 0.094 mL of diisopropylethyl amine and 0.065grams of the material from 37a. The mixture was stirred 20 minutes atambient temperature and 1 hour at 50 C. The reaction was diluted withdichloromethane and washed with brine. The aqueous was extracted 3 timeswith dichloromethane. All the extracts were combined, dried over MgSO₄and the volatiles were removed under reduced pressure. The material waschromatographed on silica gel eluting with 20% ehtyl acetate in hexanesaffording the title compound. LRMS found (M+H)⁺=568.

(39b) To 0.075 grams of material from example 39a in 2 mL oftetrahydrofuran and 2 mL of water was added 0.028 grams of lithiumhydroxide monohydrate. The reaction was stirred 1 hour at ambienttemperature at which time 0.66 mL of 1.00 M HCl was added and themixture was extracted three times with ethyl acetate. All of theextracts were combined, washed with brine, dried over MgSO₄ and thevolatiles were removed under reduced pressure affording the titlecompound. LRMS found (M+H)⁺=554.

(39c) To 0.075 grams of material from example 39b in 2 mL ofdimethylformamide was added 0.104 mL of N-methylmorpholine, 0.047 gramsof hydroxylamine hydrochloride and 0.066 grams of BOP. After stirringfor 48 hours at ambient temperature the material was poured intosaturated aqueous sodium bicarbonate and extracted three times withethyl acetate. All the extracts were combined, washed with brine, driedover MgSO4 and the volatiles were removed under reduced pressure. Thematerial was purified by reverse phase C-18 HPLC followed by ethertriteration affording the title material as the TFA salt. LRMS found(M+H)⁺=569.

Example 40(3R)-N-hydroxy-2-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)hexahydro-3-pyridazinecarboxamidebis-trifluoroacetic acid salt

(40a) To 0.018 grams of material from example 39c was added 1 mL of 32%hydrogen bromide in acetic acid. The reaction was stirred one hour atambient temperature and the volatiles were removed under reducedpressure. The material was purified by C-18 reverse phase HPLC affordingthe title compound. LRMS found (M+H)⁺=435.

Example 41(3R)-N-hydroxy-2-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-1,2,3,4-tetrahydro-3-isoguinolinecarboxamidetrifluoroacetic acid salt

(41a) To 0.245 grams of compound from example 37a in 7.5 mL ofdichloroethane was added 0.47 mL of diisopropylethyl amine and 0.156grams of tert-butyl (3R)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate.The mixture was stirred 20 minutes at ambient temperature and 2 hours at55° C. The reaction was diluted with dichloromethane and washed withbrine. The aqueous was extracted 3 times with dichloromethane. All theextracts were combined, dried over MgSO₄ and the volatiles were removedunder reduced pressure affording the title compound. LRMS found(M+H)⁺=523.

(41b) To 0.110 grams of material from example 41a was added 1 ml ofdichloromethane and 1 mL of trifluoroacetic acid. The reaction wasstirred 2 hours at ambient temperature and the volatiles were removedunder reduced pressure and the resulting material was purified by C-18reverse phase HPLC affording the title compound. LRMS found (M+H)⁺=467.

(41c) To 0.085 grams of material from example 41b in 2 mL ofdimethylformamide was added 0.12 mL of N-methylmorpholine, 0.051 gramsof hydroxylamine hydrochloride and 0.078 grams of BOP. After stirringfor 20 hours at ambient temperature the material was poured intosaturated aqueous sodium bicarbonate and extracted three times withethyl acetate. All the extracts were combined, washed with brine, driedover MgSO4 and the volatiles were removed under reduced pressure. Thematerial was purified by reverse phase C-18 HPLC affording the titlematerial as the TFA salt. LRMS found (M+H)⁺=482.

Example 42 2-((R/S)-2-phenylbutyramido)-N-hydroxy-(R)-propionamide (42a)2-t-Bulyloxycarbonylamino-N-benzyloxy-(R)-propionamide

To a solution of t-Boc-D-alanine (5.68 g, 30 mmol) andO-benzylhydroxylamine hydrochloride (5.1 g, 32 mmol) in DMF (30 mL)cooled in an ice bath was added BOP (13.7 g, 31 mmol) followed bydiisopropylethylamine (17.4 mL, 100 mmol). The solution was stirred for5 hours, diluted with EtOAc, washed with brine, sodium bicarbonate,brine, citric acid and brine, dried (MgSO4), and concentrated.Crystallization from EtOAc/hexane gave the O-benzylhydroxamate product(6.2 g, 70%) as a solid. MS (ESI): (M+H)⁺=295.1.

(42b) 2-Amino-N-benzyloxy-(R)-propionamide HCl salt

The above compound (4.5 g, 16.18 mmol) was treated with 4 N HCl indioxane (50 mL) for 1 hour and the solution was concentrated to affordthe HCl salt (3.8 g, 100%) as a solid. MS (CI—NH₃): (M+H)⁺=195.

(42c) 2-((R/S)-2-Phenylbutyramido)-N-benzyloxy-(R)-propionamide

To a solution of 2-amino-N-benzyloxy-(R)-propionamide HCl Salt (200 mg,0.868 mmol) and (R,S)-2-phenylbutyric acid (143 mg, 0.868 mmol) in 3 mLDMF cooled in an ice bath was added BOP (384 mg, 0.868 mmol) followed byDIEA (0.7 mL, 4 mmol). After stirring for 1 hour at room temperature,the solution was diluted with EtOAC, washed with NaHCO₃ and brine, driedover MgSO₄, and concentrated. Purification on a silica gel column using5% MeOH in CH₂Cl₂ gave the amide product (260 mg, 88%) as a solid. MS(ESI): (M−H)⁻=339.1.

(42d) 2-((R/S)-2-Phenylbutyramido)-N-hydroxy-(R)-propionamide

2-((R,S)-2-Phenylbutyramido)-N-benzyloxy-(R)-propionamide (230 mg, 0.676mmol) in 20 mL MeOH was hydrogenated at 50 psi in the presence of 5% Pdon BaSO₄ (230 mg) for a period of 5 hours. The catalyst was filteredoff, the solution evaporated off under reduced pressure, and the residuetriturated with ether to afford the hydroxamate compound (110 mg, 67%)as a solid. MS (ESI): (M−H)⁻=249.0.

Example 432-((R/S)-α-Methyl-4-isobutylphenylacetamido)-N-hydroxy-(R)-propionamide

This compound was synthesized by coupling2-amino-N-benzyloxy-(R)-propionamide HCl salt 42b with(R/S)-α-methyl-4-isobutylphenylacetic acid followed by hydrogenationusing the procedures as described in Example 42. MS (ESI): (M−H)⁻=291.0.

Example 442-((R/S)-2-Fluoro-α-methyl-4-biphenylacetamido)-N-hydroxy-(R)-propionamide

This compound was synthesized by coupling2-amino-N-benzyloxy-(R)-propionamide HCl salt 42b with(R/S)-2-fluoro-α-methyl-4-biphenylacetic acid (flurbiprofen, Sigma)followed by hydrogenation using the procedures as described in Example42. MS (ESI): (M−H)⁻=329.0.

Example 452-[N-Methyl-N-((R/S)-α-Methyl-4-benzyloxyphenylacetylamino)]-N-hydroxy-(R)-propionamide(45a) Methyl (R/S)-α-Methyl-4-benzyloxyphenylacetate

Lithium diisopropylamide (LDA) was prepared by the addition of 2.5 Mn-butyllithium (4.8 mL) in hexane to a solution of diisopropylamine(1.68 mL, 12 mmol) in THF (25 mL) at −78° C. followed by stirring at 0°C. for 20 min. A solution of methyl 4-benzyloxyphenylacetate (2.56 g, 10mmol) in THF (30 mL) was cooled to −78° C. and to it was added theprepared LDA solution. The mixture was stirred at −78° C. for 1 hour andiodomethane (1.25 mL, 20 mmol) was added. The mixture was allowed towarm to 0° C., stirred for an additional 1.5 hours at 0° C., quenchedwith MeOH and concentrated. The residue was taken up in EtOAc and thesolution was washed with citric acid and brine, dried (MgSO₄) andconcentrated. Chromatography on a silica gel column (35% EtOAc/hexane)afforded the α-methylated product (2.6 g, 95%) as a solid. MS (CI—NH₃):(M+H)⁺=271.

(45b) (R/S)-α-Methyl-4-benzyloxyphenylacetic Acid

To a solution of methyl (R/S)-α-methyl-4-benzyloxyphenylacetate 45a (2.7g, 10 mmol) in MeOH (25 mL) was added 1 N LiOH (15 mL). The mixture wasstirred for 2 hour and concentrated. EtOAc was added followed by 1 N HCl(10 mL). The organic layer was separated and washed with brine, dried(MgSO₄), and concentrated to afford the carboxylic acid (2.3 g, 90%) asa solid. MS (CI—NH₃): (M+H+NH₃)⁺=274.

(45c) Methyl2-[N-Methyl-N-((R/S)-α-methyl-4-benzyloxyphenylacetyl)amino]-(R)-propionate

To a solution of (R/S)-α-methyl-4-benzyloxyphenylacetic acid 45b (300mg, 1.17 mmol) and N-methyl-D-alanine methyl ester (200 mg, 1.3 mmol) inDMF (5 mL) cooled in an ice bath was added BOP (531 mg, 1.2 mmol)followed by DIEA (0.7 mL, 4 mmol). The mixture was stirred at roomtemperature for 5 hours. EtOAc was added and the solution washed withNaHCO₃, brine, citric acid and brine, dried (MgSO₄), and concentrated.Purification on a silica gel column (40% EtOAc/hexane) gave the amideproduct (398 mg, 99%) as a solid. MS (CI—NH₃): (M+H)⁺=356.

(45d)2-[N-Methyl-N-((R/S)-α-methyl-4-benzyloxyphenylacetyl)amino]-(R)-propionicAcid

To a solution of methyl2-[N-methyl-N-((R/S)-α-methyl-4-benzyloxyphenylacetyl)amino]-(R)-propionate45c (380 mg, 1.1 mmol) in THF (10 mL) was added 1 N LiOH (2 mL). Thesolution was stirred for 1 h and acidified with 1 N HCl to pH 3. EtOAcwas added and the organic layer was separated, washed with brine, dried(MgSO₄) and concentrated to afford the carboxylic acid (360 mg, 98%) asa solid. MS (CI—NH₃): (M+H)⁺=342.

(45e)2-[N-Methyl-N-((R/S)-α-methyl-4-benzyloxyphenylacetylamino)]-N-hydroxy-(R)-propionamide

A solution of2-[N-methyl-N-((R/S)-α-methyl-4-benzyloxyphenylacetyl)amino]-(R)-propionicacid (340 mg, 1.0 mmol) and N-hydroxylamine hydrochloride (100 mg, 1.4mmol) in 5 mL DMF was cooled in an ice bath and to it was added BOP (530mg, 1.2 mmol) followed by DIEA (0.7 mL, 4 mmol). The mixture was stirredat room temperature for 1 hour. EtOAc was added and the solution washedwith brine three times, dried (MgSO₄) and concentrated. Purification onreversed phase HPLC afforded the hydroxamate product (110 mg, 31%) as awhite powder after lyophilization. MS (ESI): (M−H)⁻=354.9.

Example 462-{N-Methyl-N-[(R/S)-α-methyl-4-(3,5-dimethylbenzyloxy)phenylacetyl]amino}-N-hydroxy-(R)-propionamide(46a) Methyl2-[N-Methyl-N-((R/S)-α-methyl-4-hydroxyphenylacetylamino)]-(R)-propionate

A solution of methyl2-[N-methyl-N-((R/S)-α-methyl-4-benzyloxyphenylacetyl)amino]-(R)-propionate45c (2.0 g, 5.6 mmol) in MeOH (20 mL) was hydrogenated under atmosphericpressure in the presence of 10% Pd/C (0.2 g) for a period of 1 hour. Thecatalyst was filtered off and the solvent was removed under reducedpressure to afford the phenol product (1.47 g, 99%) as a solid. MS(CI—NH₃): (M+H)⁺=266.

(46b) Methyl2-{N-Methyl-N-[(R/S)-α-methyl-4-(3,5-dimethylbenzyloxy)phenylacetyl]amino}-(R)-propionate

A solution of methyl2-[N-methyl-N-((R/S)-α-methyl-4-hydroxyphenylacetylamino)]-(R)-propionate46a (300 mg, 1.13 mmol), 3,5-dimethylbenzylbromide (300 mg, 1.5 mmol)and potassium carbonate (550 mg, 4 mmol) in DMF (10 mL) was heated at80° C. with stirring overnight. Insoluble material was filtered off andthe filtrate diluted with EtOAc. The solution was washed with brine,dried over MgSO₄ and concentrated. The residue was purified on a silicagel column by eluting with EtOAc/hexane (1:1) to afford the etherproduct (110 mg, 25%) as a solid. MS (CI—NH₃): (M+H)⁺=384.

(46c)2-{N-Methyl-N-[(R/S)-α-methyl-4-(3,5-dimethylbenzyloxy)phenylacetyl]amino}-(R)-propionicAcid

A solution of methyl2-{N-methyl-N-[(R/S)-α-methyl-4-(3,5-dimethylbenzyloxy)phenylacetyl]amino}-(R)-propionate46b (107 mg, 0.28 mmol) in THF (5 mL) was treated with 1 N LiOH (1 mL)for 40 min. The solution was acidified with 1 N HCl (1.5 mL) andextracted with EtOAc three times. The combined organic layers werewashed with brine, dried over MgSO₄ and concentrated to give the acid(103 mg, 100%) as a solid. MS (CI—NH₃): (M+H)⁺=370.

(46d)2-{N-Methyl-N-[(R/S)-α-methyl-4-(3,5-dimethylbenzyloxy)phenylacetyl]amino}-N-hydroxy-(R)-propionamide

A solution of2-{N-methyl-N-[(R/S)-α-methyl-4-(3,5-dimethylbenzyloxy)phenylacetyl]amino}-(R)-propionicAcid 46c (100 mg, 0.27 mmol) and N-hydroxylamine (69 mg, 1 mmol) in DMF(5 mL) was cooled in an ice bath and to it was added BOP (127 mg, 0.28mol) followed by DIEA (0.34 mL, 2 mmol). The mixture was stirredovernight and diluted with EtOAc. The solution was washed with NaHCO₃and brine, dried over MgSO₄ and concentrated. The residue was purifiedusing reversed phase HPLC to afford the hydroxamate (54 mg, 52%) as apowder after lyophilization. MS (ESI): (M+TFA−H)⁻=496.9.

Example 472-{N-Methyl-N-[(R/S)-α-methyl-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-N-hydroxy-(R)-propionamide

This compound was prepared using procedures similar to those asdescribed in Example 46. MS (ESI): (M+TFA−H)⁻=605.

Example 482-{N-Methyl-N-[(R/S)-α-(methylaminocarbonylmethyl)-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-N-hydroxy-(R)-propionamide(48a) Methyl (R/S)-α-t-Butoxycarbonylmethyl-4-benzyloxyphenylacetate

Lithium diisopropylamide (LDA) was prepared by the addition of 2.5 Mn-butyllithium in hexane (8.4 mL) to a solution of diisopropylamine(2.94 mL, 21 mmol) in THF (30 mL) at −78° C. followed by stirring at 0°C. for 20 min. A solution of methyl 4-benzyloxyphenylacetate (4.8 g,18.7 mmol) in THF (50 mL) was cooled to −78° C. and to it was added theprepared LDA solution. The mixture was stirred at −78° C. for 1 h andt-butyl bromoacetate (3.1 mL, 21 mmol) in THF (20 mL) was added. Themixture was allowed to warm to 0° C., stirred for an additional 1.5 h at0° C., quenched with MeOH and concentrated in vacuo. The residue wastaken up in EtOAc and the solution was washed with citric acid andbrine, dried over MgSO₄ and concentrated. Purification on a silica gelcolumn by eluting with 40% EtOAc/hexane afforded the desired product(6.0 g, 86%) as a solid. MS (CI—NH₃): (M+H)⁺=371.

(48b) (R/S)-α-t-Butoxycarbonylmethyl-4-benzyloxyphenylacetic Acid

A solution of methyl(R/S)-α-t-butoxycarbonylmethyl-4-benzyloxyphenylacetate (5.92 g, 16mmol) 48a in MeOH (50 mL) was treated with 1 N LiOH (32 mL) for 3 hoursand MeOH was removed by concentration in vacuo. EtOAc was added and thesolution was acidified with citric acid to pH 3. The organic layer wasseparated and the water solution was extracted with EtOAc one more time.The combined organic layers were washed with brine, dried over MgSO₄ andconcentrated to afford the acid (4.8 g, 84%) as a solid. MS (CI—NH₃):(M+H)⁺=357.

(48c) Methyl2-[N-Methyl-N-((R/S)-α-t-butoxycarbonylmethyl-4-benzyloxyphenylacetyl)amino]-(R)-propionate

To a solution of (R/S)-α-t-butoxycarbonylmethyl-4-benzyloxyphenylaceticacid 48b (4.8 g, 13.48 mmol) and methyl N-methyl-D-alaninatehydrochloride (2.9 g, 18.9 mmol) in DMF (30 mL) cooled in an ice bathwas added BOP (6.56 g, 14.83 mmol) followed by DIEA (16.5 mL, 94.5 mmol)and the solution was stirred overnight. EtOAc was added and the solutionwas washed with NaHCO₃ and brine, dried over MgSO₄, and concentrated.The residue was purified on a silica gel column by eluting with 40%EtOAc/hexane to give the desired product (3.0 g, 49%) as a solid. MS(CI—NH₃): (M+H)⁺=456.

(48d) Methyl2-[N-Methyl-N-((R/S)-α-t-butoxycarbonylmethyl-4-hydroxyphenylacetyl)amino]-(R)-propionate

A solution of methyl2-[N-methyl-N-((R/S)-α-t-butoxycarbonylmethyl-4-benzyloxyphenylacetyl)amino]-(R)-propionate48c (3.0 g, 6.59 mmol) in MeOH (75 mL) was hydrogenated underatmospheric pressure using 10% Pd/C (0.6 g) as a catalyst for a periodof 4.5 hours. The catalyst was filtered off and the solvent was removedunder reduced pressure. The residue was purified on a silica gel columnusing 40% EtOAc/hexane as an eluent to afford the phenol product (1.5 g,62%) as a solid. MS (CI—NH₃): (M+H)⁺=366.

(48e) Methyl2-{N-Methyl-N-[(R/S)-α-t-butoxycarbonylmethyl-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-(R)-propionate

A solution of methyl2-UN-methyl-N-((R/S)-α-t-butoxycarbonylmethyl-4-hydroxyphenylacetyl)amino]-(R)-propionate48d (1.5 g, 4.1 mmol) and 3,5-bistrifluoromethylbenzyl bromide (1.3 g,4.2 mmol) in DMF (10 mL) was stirred at 60° C. overnight in the presenceof K₂CO₃ (1.14 g, 8 mmol). After cooling to room temperature, EtOAc wasadded and the solution was washed with brine three times, dried overMgSO₄, and concentrated. Purification on a silica gel column by elutingwith 40% EtOAc/hexane afforded the product (1.46 g, 60%) as a solid. MS(CI—NH₃): (M+H)⁺=592.

(48f) Methyl2-{N-Methyl-N-[(R/S)-α-hydroxycarbonylmethyl-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-(R)-propionate

Methyl2-{N-methyl-N-[(R/S)-α-t-butoxycarbonylmethyl-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-(R)-propionate48e (1.46 g, 2.47 mmol) was treated with 50% TFA in CH₂Cl₂ (20 mL) for 1hour and the solution was concentrated in vacuo to give the acid (1.46g, 100%) as a syrup. MS (ESI): (M+H)⁺=535.9.

(48g) Methyl2-{N-Methyl-N-[(R/S)-α-methylaminocarbonylmethyl-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-(R)-propionate

A solution of methyl2-{N-methyl-N-[(R/S)-α-hydroxycarbonylmethyl-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-(R)-propionate48f (0.3 g, 0.56 mmol), methylamine hydrochloride (68 mg, 1 mmol) andDIEA (0.35 mL, 2 mmol) in DMF (5 mL) was cooled in an ice bath and to itwas added BOP (265 mg, 0.6 mmol). After stirring at room temperature for1 hour, EtOAc was added and the solution was washed with NaHCO₃ andbrine, dried over MgSO₄, and concentrated to give the amide (312 mg,100%) as a solid. MS (ESI): (M+Na)⁺=571.8.

(48h)2-{N-Methyl-N-[(R/S)-α-methylaminocarbonylmethyl-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-(R)-propionicAcid

Methyl2-{N-methyl-N-[(R/S)-α-methylaminocarbonylmethyl-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-(R)-propionate48g (310 mg, 0.56 mmol) was dissolved in MeOH (5 mL) and 1 N LiOH (2 mL)was added. The solution was stirred for 1 hour and concentrated invacuo. EtOAc was added and the solution was acidified with 1 N HCl,washed with brine, dried over MgSO₄, and concentrated to afford the acid(280 mg, 92%) as a solid. MS (ESI): (M+H)⁺=535.8.

(48i)2-{N-Methyl-N-[(R/S)-α-(methylaminocarbonylmethyl)-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-N-hydroxy-(R)-propionamide

To a solution of2-{N-methyl-N-[(R/S)-α-methylaminocarbonylmethyl-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-(R)-propionicacid 7h (280 mg, 0.52 mmol), hydroxylamine hydrochloride (100 mg, 1.4mmol) and DIEA (0.5 mL, 2.87 mmol) in DMF (5 mL) cooled in an ice bathwas added BOP (265 mg, 0.6 mmol) and the solution was stirred at roomtemperature for 1 hour. EtOAc was added and the solution was washed withbrine three times, dried over MgSO₄ and concentrated. The residue waspurified on reversed phase HPLC to afford the hydroxamate (135 mg, 47%)as a powder after lyophilization. MS (ESI): (M+TFA−H)⁻=663.5.

Example 492-{N-Methyl-N-[(R/S)-α-(aminocarbonylmethyl)-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-N-hydroxy-(R)-propionamide

This compound was prepared using the procedures as described in Example48. MS (ESI): (M−H)⁻=533.9.

Example 502-{N-Methyl-N-[(R/S)-α-(1-piperazinocarbonylmethyl)-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-N-hydroxy-(R)-propionamide

This compound was prepared using procedures similar to those describedin Example 48. MS (ESI): (M+H)⁺=605.0.

Example 51(2R)-2-[(amino{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)amino]-N-hydroxy-4-methylpentanamide

(51a) N-Boc-4-hydroxyphenyl glycine methyl ester (8.24 g, 29.3 mmol) and4-chloromethyl 2-methyl quinoline (9.10 g, 40.0 mmol) were combined inacetone 150 ml, potassium carbonate (12.5 g, 90.0 mmol) and potassiumiodide (4.3 g, 26 mmol) were added and the reaction was heated to refluxfor 5hr. The reaction was allowed to cool, filtered through celite andwas concentrated to give an oil. The product was purified by flashchromatography on silica gel eluting ethyl acetate: hexane (60:40, v:v)to give the N-Boc-4-(2-methyl-4-quinoline)methoxyphenyl glycine methylester (8.7 g, 68%) as a yellow foam MS (M−C₄H₈+H)⁺=381.

(51b) The N-Boc-4-(2-methyl-4-quinoline)methoxyphenyl glycine methylester (1.0 g, 2.3 mmol)was dissolved in methanol 20ml, and lithiumhydroxide hydrate (0.11 g, 2.6 mmol) dissolved in water 10 m was added.The reaction was stirred at RT for 2hs. This was concentrated in vacuoand the resulting aqueous residue was diluted with water 20 ml washedwith ethyl ether (2×), then made neutral with HCl. The aqueous layer wasextracted with ethyl acetate (2×). The combined ethyl acetate layerswere washed with brine dried over magnesium sulfate and concentrated togive the N-Boc-4-(2-methyl-4-quinoline)methoxyphenyl glycine carboxylicacid (0.97 g, 99%) as a light yellow solid MS (M+H) 423.

(51c) The N-Boc-4-(2-methyl-4-quinoline)methoxyphenyl glycine carboxylicacid (0.30 g, 0.71 mmol) was dissolved in DMF 5ml, the N-methylmorpholine (0.5 ml) and TBTU (0.28 g, 0.87 mmol) were added at RT andstirred for 15 minutes before the D-leucine methyl ester(0.15 g, 0.83mmol) was added. The reaction was complete after stirring for 1.5 hr wasdiluted with water, and extracted with ethyl acetate. The combinedorganic layer was washed with brine, dried over magnesium sulfate andconcentrated to a foam. The product was purified by flash chromatographyon silica gel eluting ethyl acetate:hexane (50:50, v:v) to giveD-leucine N-Boc-4-(2-methyl-4-quinoline)methoxyphenyl glycine methylester (0.325 g, 84%) as a clear oil MS (M+H)=550.

(51d) The D-leucine N-Boc-4-(2-methyl-4-quinoline)methoxyphenylglycinemethyl ester (0.325 g,0.58 mmol) was dissolved in methylene chloride 6ml and trifluoroacetic acid 2 ml under nitrogen at RT. The reaction wasstirred for 1.5 hs and was concentrated to give the D-leucine4-(2-methyl-4-quinoline)methoxyphenylglycine methyl ester bistrifluoroacetic acid salt (0.44 g, 100%) as a clear oil MS (M+H)=450.

(51e) The D-leucine 4-(2-methyl-4-quinoline)methoxyphenyl glycine methylester bis trifluoroacetic acid salt (0.435 g, 0.96 mmol) was dissolvedin a solution of potassium hydroxide:hydroxylaminehydrochloride:methanol (1.76M) 5 ml under nitrogen at RT. The reactionwas stirred for 40 minutes, concentrated in vacuo, the residue dissolvedin acetonitrile:water (80:20) and made acidic with trifluoroacetic acid.The product was purified by reverse phase HPLC eluting anacetonitrile:water:TFA gradient on a Vydac C-18 column to give the titlecompound (0.135 g, 33%) as a white solid MS (M+H)=451.

Example 522-[(amino{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)amino]-N-hydroxy-2-methylpropanamide

(52a) Following the procedures analogous to that used for thepreparation of example 51 but using 2-methyl alanine methyl ester instep 1c, the title compound was prepared (0.09 g, 40%) as a white solidMS (M+H)=423.

TABLE 1

Ex 1-4, 6-10, 18 20-21, 25-30

Ex 5

Ex 11 (n = 1) Ex 12 (n = 2)

Ex 13 (R⁴ = OH) Ex 14 & 31 (R⁴ = NHBoc) Ex 51 (R⁴ = NH₂)

Ex 15

Ex 16

Ex 17, 19, 22-24

Ex. 32

Ex 33 (n = 1) Ex 36 (n = 2)

Ex 34

Ex 35

Ex 37-38

Ex 39-40

Ex 41

Ex 42

Ex 43-47

Ex 48 (R = NHMe) Ex 49 (R = NH₂) Ex 50(R = 1-piperazinyl)

Ex 52 Ex MS # R¹ R³ R^(b′) (M + H)⁺ 1 i-propyl 4-methylphenyl H 289 2i-propyl 4-methoxyphenyl H 305 3 2-(methyl- 4-methoxyphenyl H 337thio)ethyl 4 2- 4-methoxyphenyl H 369 (methyl- sulfonyl) ethyl 5i-propyl phenyl methyl 291 6 i-propyl phenyl methyl 289 7 i-propyl4-methylphenyl methyl 303 8 i-propyl 4-methoxyphenyl methyl 319 9i-propyl 4-chlorophenyl methyl 323 10 i-propyl 2,4-dichlorophenyl methyl357 11 i-propyl 4-chlorophenyl methyl 337 12 i-propyl phenyl methyl 31713 i-propyl phenyl methyl 279 14 i-propyl phenyl methyl 380 15 —2,4-dichlorophenyl — (M − H)⁻ 355 16 — 2,4-dichlorophenyl — (M − H)⁻ 34117 i-propyl 4-methoxyphenyl methyl (M − H)⁻ 293 18 methyl4-[(2,4-dimethoxyphenyl) methyl (M − H)⁻ methoxy]phenyl 395 19 methyl4-methoxyphenyl methyl (M − H)⁻ 265 20 methyl 4-[(2- methyl (M − H)⁻naphthalenyl)methoxy]phenyl 417 21 methyl 4-[(4- methyl (M − H)⁻pyridinyl)methoxy]phenyl 368 22 i-propyl 4-(phenylmethoxy)phenyl methyl(M − H)⁻ 395 23 i-propyl 4-[(3,5-dimethylphenyl) methyl (M − H)⁻methoxy]phenyl 423 24 i-propyl 4-[(1- methyl (M − H)⁻benzotriazolyl)methoxy]phenyl 436 25 methyl 4-[(3-phenyl-5- methyl (M −H)⁻ isoxazolyl)methoxy]phenyl 434 26 methyl 4-(2-propynyloxy)phenylmethyl (M − H)⁻ 315 27 methyl 4-[[3-(4-fluorophenyl)-5- methyl 452isoxazolyl]methoxy]phenyl 28 methyl 4-[(3-propyl-5- methyl (M − H)⁻isoxazolyl)methoxy]phenyl 400 29 isobutyl 4-[(2-methyl-4- propyl 504quinolinyl)methoxy]phenyl 30 isobutyl 4-[(2-methyl-4- 3- 587quinolinyl)methoxy]phenyl (cyclopent ylamino) propyl 31 methyl4-(phenylmethoxy)phenyl methyl (M − H)⁻ 456 32 methyl4-(phenylmethoxy)phenyl H 426 33 — 4-[(2-methyl-4- — 420quinolinyl)methoxy]phenyl 34 — 4-[(2-methyl-4- — 420quinolinyl)methoxy]phenyl 35 — 4-[(2-methyl-4- — 480quinolinyl)methoxy]phenyl 36 — 4-[(2-methyl-4- — 434quinolinyl)methoxy]phenyl 37 — 4-[(2-methyl-4- t- 535quinolinyl)methoxy]phenyl butoxycar bonyl 38 — 4-[(2-methyl-4- H 435quinolinyl)methoxy]phenyl 39 — 4-[(2-methyl-4- benzyloxy 569quinolinyl)methoxy]phenyl carbonyl 40 — 4-[(2-methyl-4- H 435quinolinyl)methoxy]phenyl 41 — 4-[(2-methyl-4- — 482quinolinyl)methoxy]phenyl 42 methyl phenyl H (M − H)⁻ 249 43 methyl4-isobutylphenyl H (M − H)⁻ 291 44 methyl 3-fluoro-4-phenylphenyl H (M −H)⁻ 329 45 methyl 4-(phenylmethoxy)phenyl methyl (M − H)⁻ 355 46 methyl4-[(3,5-dimethylphenyl) methyl (M + methoxy]phenyl TFA- H)⁻499 47 methyl4-[[3,5- methyl (M + bis(trifluoromethyl)phenyl] TFA- methoxy]phenylH)⁻605 48 methyl 4-[[3,5- methyl (M + bis(trifluoromethyl)phenyl] TFA-methoxy]phenyl H)⁻664 49 methyl 4-[[3,5- methyl (M − H)⁻bis(trifluoromethyl)phenyl] 534 methoxy]phenyl 50 methyl 4-[[3,5- methyl(M − H)⁻ bis(trifluoromethyl)phenyl] 605 methoxy]phenyl 51 isobutyl4-[(2-methyl-4- H 451 quinolinyl)methoxy)phenyl 52 — 4-[(2-methyl-4- H423 quinolinyl)methoxy]phenyl

The following tables contain representative examples of the presentinvention. Each entry in each table is intended to be paired with eachformula at the start of the table. For example, in Table 2, example 1 isintended to be paired with each of formulae A1-JJ2.

TABLE 2

Al (n = 1) A2 (n = 2)

B1 (n = 1) B2 (n = 2)

C1 (n = 1) C2 (n = 2)

D1 (n = 1) D2 (n = 2)

E1 (n = 1) E2 (n = 2)

F2 (n = 1) F2 (n = 2)

G1 (n = 1) G2 (n = 2)

H1 (n = 1) H2 (n = 2)

I1 (n = 1) I2 (n = 2)

J1 (n = 1) J2 (n = 2)

K1 (n = 1) K2 (n = 2)

L1 (n = 1) L2 (n = 2)

M1 (n = 1) M2 (n = 2)

N1 (n = 1) N2 (n = 2)

O1 (n = 1) O2 (n = 2)

P1 (n = 1) P2 (n = 2)

Q1 (n = 1) Q2 (n = 2)

R1 (n = 1) R2 (n = 2)

S1 (n = 1) S2 (n = 2)

T1 (n = 1) T2 (n = 2)

U1 (n = 1) U2 (n = 2)

V1 (n = 1) V2 (n = 2)

W1 (n = 1) W2 (n = 2)

X1 (n = 1) X2 (n = 2)

Y1 (n = 1) Y2 (n = 2)

Z1 (n = 1) Z2 (n = 2)

AA1 (n = 1) AA2 (n = 2)

BB1 (n = 1) BB2 (n = 2)

CC1 (n = 1) CC2 (n = 2)

DD1 (n = 1) DD2 (n = 2)

EE1 (n = 1) EE2 (n = 2)

FF1 (n = 1) FF2 (n = 2)

GG1 (n = 1) GG2 (n = 2)

HH1 (n = 1) HH2 (n = 2)

II1 (n = 1) II2 (n = 2)

JJ1 (n = 1) JJ2 (n = 2) Ex# R^(b) R^(3’) 1 H H 2 methyl H 3 chloro H 4 Hmethyl 5 methyl methyl 6 chloro methyl 7 H ethyl 8 methyl ethyl 9 chloroethyl 10 H isopropyl 11 methyl isopropyl 12 chloro isopropyl 13 H phenyl14 methyl phenyl 15 chloro phenyl 16 H benzyl 17 methyl benzyl 18 chlorobenzyl 19 H 2-phenylethyl 20 methyl 2-phenylethyl 21 chloro2-phenylethyl 22 H 2-(2-methylphenyl)ethyl 23 methyl2-(2-methylphenyl)ethyl 24 chloro 2-(2-methylphenyl)ethyl 25 H2-(3-methylphenyl)ethyl 26 methyl 2-(3-methylphenyl)ethyl 27 chloro2-(3-methylphenyl)ethyl 28 H 2-(2,6-dimethylphenyl)ethyl 29 methyl2-(2,6-dimethylphenyl)ethyl 30 chloro 2-(2,6-dimethylphenyl)ethyl 31 H2-(3,5-dimethylphenyl)ethyl 32 methyl 2-(3,5-dimethylphenyl)ethyl 33chloro 2-(3,5-dimethylphenyl)ethyl 34 H 2-(3-amino-5-methylphenyl)ethyl35 methyl 2-(3-amino-5-methylphenyl)ethyl 36 chloro2-(3-amino-5-methylphenyl)ethyl 37 H 2-(pyridin-4-yl)ethyl 38 methyl2-(pyridin-4-yl)ethyl 39 chloro 2-(pyridin-4-yl)ethyl 40 H2-(2,6-dimethylpyridin-4-yl)ethyl 41 methyl2-(2,6-dimethylpyridin-4-yl)ethyl 42 chloro2-(2,6-dimethylpyridin-4-yl)ethyl 43 H 2-(3,5-dimethylpyridin-4-yl)ethyl44 methyl 2-(3,5-dimethylpyridin-4-yl)ethyl 45 chloro2-(3,5-dimethylpyridin-4-yl)ethyl 46 H styryl 47 methyl styryl 48 chlorostyryl 49 H hydroxy 50 methyl hydroxy 51 chloro hydroxy 52 H methoxy 53methyl methoxy 54 chloro methoxy 55 H ethoxy 56 methyl ethoxy 57 chloroethoxy 58 H isopropyloxy 59 methyl isopropyloxy 60 chloro isopropyloxy61 H tert-butoxy 62 methyl tert-butoxy 63 chloro tert-butoxy 64 Hcyclohexyloxy 65 methyl cyclohexyloxy 66 chloro cyclohexyloxy 67 Hphenoxy 68 methyl phenoxy 69 chloro phenoxy 70 H o-methylphenoxy 71methyl o-methylphenoxy 72 chloro o-methylphenoxy 73 H m-methylphenoxy 74methyl m-methylphenoxy 75 chloro m-methylphenoxy 76 H cinnamyloxy 77methyl cinnamyloxy 78 chloro cinnamyloxy 79 H benzyloxy 80 methylbenzyloxy 81 chloro benzyloxy 82 H phenoxymethyl 83 methyl phenoxymethyl84 chloro phenoxymethyl 85 H o-methylbenzyloxy 86 methylo-methylbenzyloxy 87 chloro o-methylbenzyloxy 88 H m-methylbenzyloxy 89methyl m-methylbenzyloxy 90 chloro m-methylbenzyloxy 91 Ho,o-dimethylbenzyloxy 92 methyl o,o-dimethylbenzyloxy 93 chloroo,o-dimethylbenzyloxy 94 H (2,6-dimethylphenoxy)methyl 95 methyl(2,6-dimethylphenoxy)methyl 96 chloro (2,6-dimethylphenoxy)methyl 97 Hm,m-dimethylbenzyloxy 98 methyl m,m-dimethylbenzyloxy 99 chlorom,m-dimethylbenzyloxy 100 H (3,5-dimethylphenoxy)methyl 101 methyl(3,5-dimethylphenoxy)methyl 102 chloro (3,5-dimethylphenoxy)methyl 103 Ho,o-dicyanobenzyloxy 104 methyl o,o-dicyanobenzyloxy 105 chloroo,o-dicyanobenzyloxy 106 H m,m-dicyanobenzyloxy 107 methylm,m-dicyanobenzyloxy 108 chloro m,m-dicyanobenzyloxy 109 H(2,6-dicyanophenoxy)methyl 110 methyl (2,6-dicyanophenoxy)methyl 111chloro (2,6-dicyanophenoxy)methyl 112 H (3,5-dicyanophenoxy)methyl 113methyl (3,5-dicyanophenoxy)methyl 114 chloro (3,5-dicyanophenoxy)methyl115 H o-amino-o-cyanobenzyloxy 116 methyl o-amino-o-cyanobenzyloxy 117chloro o-amino-o-cyanobenzyloxy 118 H m-amino-m-cyanobenzyloxy 119methyl m-amino-m-cyanobenzyloxy 120 chloro m-amino-m-cyanobenzyloxy 121H o-amino-o-nitrobenzyloxy 122 methyl o-amino-o-nitrobenzyloxy 123chloro o-amino-o-nitrobenzyloxy 124 H m-amino-m-nitrobenzyloxy 125methyl m-amino-m-nitrobenzyloxy 126 chloro m-amino-m-nitrobenzyloxy 127H p-amino-m,m-dimethylbenzyloxy 128 methyl p-amino-m,m-dimethylbenzyloxy129 chloro p-amino-m,m-dimethylbenzyloxy 130 H o-amino-o-methylbenzyloxy131 methyl o-amino-o-methylbenzyloxy 132 chloroo-amino-o-methylbenzyloxy 133 H m-amino-m-methylbenzyloxy 134 methylm-amino-m-methylbenzyloxy 135 chloro m-amino-m-methylbenzyloxy 136 Ho-cyano-o-methylbenzyloxy 137 methyl o-cyano-o-methylbenzyloxy 138chloro o-cyano-o-methylbenzyloxy 139 H m-cyano-m-methylbenzyloxy 140methyl m-cyano-m-methylbenzyloxy 141 chloro m-cyano-m-methylbenzyloxy142 H o-cyano-o-nitrobenzyloxy 143 methyl o-cyano-o-nitrobenzyloxy 144chloro o-cyano-o-nitrobenzyloxy 145 H (2-cyano-6-nitrophenoxy)methyl 146methyl (2-cyano-6-nitrophenoxy)methyl 147 chloro(2-cyano-6-nitrophenoxy)methyl 148 H m-cyano-m-nitrobenzyloxy 149 methylm-cyano-m-nitrobenzyloxy 150 chloro m-cyano-m-nitrobenzyloxy 151 H(3-cyano-5-nitrophenoxy)methyl 152 methyl (3-cyano-5-nitrophenoxy)methyl153 chloro (3-cyano-5-nitrophenoxy)methyl 154 H m,m-dimethoxybenzyloxy155 methyl m,m-dimethoxybenzyloxy 156 chloro m,m-dimethoxybenzyloxy 157H m,m-dichlorobenzyloxy 158 methyl m,m-dichlorobenzyloxy 159 chlorom,m-dichlorobenzyloxy 160 H (3,5-dichlorophenoxy)methyl 161 methyl(3,5-dichlorophenoxy)methyl 162 chloro (3,5-dichlorophenoxy)methyl 163 Hm,m-dibromobenzyloxy 164 methyl m,m-dibromobenzyloxy 165 chlorom,m-dibromobenzyloxy 166 H m,m-bis(trifluoromethyl)benzyloxy 167 methylm,m-bis(trifluoromethyl)benzyloxy 168 chlorom,m-bis(trifluoromethyl)benzyloxy 169 H[3,5-bis(trifluoromethyl)phenoxy]methyl 170 methyl[3,5-bis(trifluoromethyl)phenoxy]methyl 171 chloro[3,5-bis(trifluoromethyl)phenoxy]methyl 172 Hm-carboxamido-m-methylbenzyloxy 173 methylm-carboxamido-m-methylbenzyloxy 174 chlorom-carboxamido-m-methylbenzyloxy 175 H(3-carboxamido-5-methylphenoxy)methyl 176 methyl(3-carboxamido-5-methylphenoxy)methyl 177 chloro(3-carboxamido-5-methylphenoxy)methyl 178 Hm-hydroxycarbonyl-m-methylbenzyloxy 179 methylm-hydroxycarbonyl-m-methylbenzyloxy 180 chlorom-hydroxycarbonyl-m-methylbenzyloxy 181 H(3-hydroxycarbonyl-5-methylphenoxy)methyl 182 methyl(3-hydroxycarbonyl-5-methylphenoxy)methyl 183 chloro(3-hydroxycarbonyl-5-methylphenoxy)methyl 184 H o-phenylbenzyloxy 185methyl o-phenylbenzyloxy 186 chloro o-phenylbenzyloxy 187 Hm-phenylbenzyloxy 188 methyl m-phenylbenzyloxy 189 chlorom-phenylbenzyloxy 190 H (naphth-1-yl)methoxy 191 methyl(naphth-1-yl)methoxy 192 chloro (naphth-1-yl)methoxy 193 H(naphth-2-yl)methoxy 194 methyl (naphth-2-yl)methoxy 195 chloro(naphth-2-yl)methoxy 196 H (2-methylnaphth-1-yl)methoxy 197 methyl(2-methylnaphth-1-yl)methoxy 198 chloro (2-methylnaphth-1-yl)methoxy 199H (4-methylnaphth-2-yl)methoxy 200 methyl (4-methylnaphth-2-yl)methoxy201 chloro (4-methylnaphth-2-yl)methoxy 202 H (pyridin-3-yl)methoxy 203methyl (pyridin-3-yl)methoxy 204 chloro (pyridin-3-yl)methoxy 205 H(pyridin-4-yl)methoxy 206 methyl (pyridin-4-yl)methoxy 207 chloro(pyridin-4-yl)methoxy 208 H (3,5-dichloropyridin-4-yl)methoxy 209 methyl(3,5-dichloropyridin-4-yl)methoxy 210 chloro(3,5-dichloropyridin-4-yl)methoxy 211 H(3,5-dimethylpyridin-4-yl)methoxy 212 methyl(3,5-dimethylpyridin-4-yl)methoxy 213 chloro(3,5-dimethylpyridin-4-yl)methoxy 214 H (1,2,3-benzotriazol-1-yl)methoxy215 methyl (1,2,3-benzotriazol-1-yl)methoxy 216 chloro(1,2,3-benzotriazol-1-yl)methoxy 217 H benzhydroxy 218 methylbenzhydroxy 219 chloro benzhydroxy 220 Hp-(1,2,3-thiadiazol-5-yl)benzyloxy 221 methylp-(1,2,3-thiadiazol-5-yl)benzyloxy 222 chlorop-(1,2,3-thiadiazol-5-yl)benzyloxy 223 H o-(tetrazol-5-yl)benzyloxy 224methyl o-(tetrazol-5-yl)benzyloxy 225 chloro o-(tetrazol-5-yl)benzyloxy226 H m-(tetrazol-5-yl)benzyloxy 227 methyl m-(tetrazol-5-yl)benzyloxy228 chloro m-(tetrazol-5-yl)benzyloxy 229 H[3-methyl-5-(tetrazol-5-yl)phenoxy]methyl 230 methyl[3-methyl-5-(tetrazol-5-yl)phenoxy]methyl 231 chloro[3-methyl-5-(tetrazol-5-yl)phenoxy]methyl 232 Hm-methyl-m-(tetrazol-5-yl)benzyloxy 233 methylm-methyl-m-(tetrazol-5-yl)benzyloxy 234 chlorom-methyl-m-(tetrazol-5-yl)benzyloxy 235 H 2-oxo-2-phenylethoxy 236methyl 2-oxo-2-phenylethoxy 237 chloro 2-oxo-2-phenylethoxy 238 Hcarbo-t-butoxymethoxy 239 methyl carbo-t-butoxymethoxy 240 chlorocarbo-t-butoxymethoxy 241 H (benzimidazol-2-yl)methoxy 242 methyl(benzimidazol-2-yl)methoxy 243 chloro (benzimidazol-2-yl)methoxy 244 H(imidazol-2-yl)methoxy 245 methyl (imidazol-2-yl)methoxy 246 chloro(imidazol-2-yl)methoxy 247 H (1,4-dimethylimidazol-5-yl)methoxy 248methyl (1,4-dimethylimidazol-5-yl)methoxy 249 chloro(1,4-dimethylimidazol-5-yl)methoxy 250 H (thiazol-4-yl)methoxy 251methyl (thiazol-4-yl)methoxy 252 chloro (thiazol-4-yl)methoxy 253 H(quinolin-2-yl)methoxy 254 methyl (quinolin-2-yl)methoxy 255 chloro(quinolin-2-yl)methoxy 256 H (1,3-benzodioxo-5-yl)methoxy 257 methyl(1,3-benzodioxo-5-yl)methoxy 258 chloro (1,3-benzodioxo-5-yl)methoxy 259H (3,5-dimethylisoxazol-4-yl)methoxy 260 methyl(3,5-dimethylisoxazol-4-yl)methoxy 261 chloro(3,5-dimethylisoxazol-4-yl)methoxy 262 H(3,5-dimethylpyrazol-1-yl)methoxy 263 methyl(3,5-dimethylpyrazol-1-yl)methoxy 264 chloro(3,5-dimethylpyrazol-1-yl)methoxy 265 H(1,3,5-trimethylpyrazol-4-yl)methoxy 266 methyl(1,3,5-trimethylpyrazol-4-yl)methoxy 267 chloro(1,3,5-trimethylpyrazol-4-yl)methoxy 268 H 4-quinolinylmethoxy 269methyl 4-quinolinylmethoxy 270 chloro 4-quinolinylmethoxy 271 H2-methyl-4-quinolinylmethoxy 272 methyl 2-methyl-4-quinolinylmethoxy 273chloro 2-methyl-4-quinolinylmethoxy 274 H 4-quinolinyloxymethyl 275methyl 4-quinolinyloxymethyl 276 chloro 4-quinolinyloxymethyl

TABLE 3

A1 (Ar = ring Σ) A2 (Ar = ring Δ) A3 (Ar = ring Φ) A4 (Ar = ring Ω) A5(Ar = ring Ψ)

B1 (Ar = ring Σ) B2 (Ar = ring Δ) B3 (Ar = ring Φ) B4 (Ar = ring Ω) B5(Ar = ring Ψ)

C1 (Ar = ring Σ) C2 (Ar = ring Δ) C3 (Ar = ring Φ) C4 (Ar = ring Ω) C5(Ar = ring Ψ)

D1 (Ar = ring Σ) D2 (Ar = ring Δ) D3 (Ar = ring Φ) D4 (Ar = ring Ω) D5(Ar = ring Ψ)

E1 (Ar = ring Σ) E2 (Ar = ring Δ) E3 (Ar = ring Φ) E4 (Ar = ring Ω) E5(Ar = ring Ψ)

F1 (Ar = ring Σ) F2 (Ar = ring Δ) F3 (Ar = ring Φ) F4 (Ar = ring Ω) F5(Ar = ring Ψ)

G1 (Ar = ring Σ) G2 (Ar = ring Δ) G3 (Ar = ring Φ) G4 (Ar = ring Ω) G5(Ar = ring Ψ)

H1 (Ar = ring Σ) H2 (Ar = ring Δ) H3 (Ar = ring Φ) H4 (Ar = ring Ω) H5(Ar = ring Ψ)

I1 (Ar = ring Σ) I2 (Ar = ring Δ) I3 (Ar = ring Φ) I4 (Ar = ring Ω) I5(Ar = ring Ψ)

J1 (Ar = ring Σ) J2 (Ar = ring Δ) J3 (Ar = ring Φ) J4 (Ar = ring Ω) J5(Ar = ring Ψ)

K1 (Ar = ring Σ) K2 (Ar = ring Δ) K3 (Ar = ring Φ) K4 (Ar = ring Ω) K5(Ar = ring Ψ)

L1 (Ar = ring Σ) L2 (Ar = ring Δ) L3 (Ar = ring Φ) L4 (Ar = ring Ω) L5(Ar = ring Ψ)

M1 (Ar = ring Σ) M2 (Ar = ring Δ) M3 (Ar = ring Φ) M4 (Ar = ring Ω) M5(Ar = ring Ψ)

N1 (Ar = ring Σ) N2 (Ar = ring Δ) N3 (Ar = ring Φ) N4 (Ar = ring Ω) N5(Ar = ring Ψ)

O1 (Ar = ring Σ) O2 (Ar = ring Δ) O3 (Ar = ring Φ) O4 (Ar = ring Ω) O5(Ar = ring Ψ)

P1 (Ar = ring Σ) P2 (Ar = ring Δ) P3 (Ar = ring Φ) P4 (Ar = ring Ω) P5(Ar = ring Ψ)

Q1 (Ar = ring Σ) Q2 (Ar = ring Δ) Q3 (Ar = ring Φ) Q4 (Ar = ring Ω) Q5(Ar = ring Ψ)

R1 (Ar = ring Σ) R2 (Ar = ring Δ) R3 (Ar = ring Φ) R4 (Ar = ring Ω) R5(Ar = ring Ψ)

S1 (Ar = ring Σ) S2 (Ar = ring Δ) S3 (Ar = ring Φ) S4 (Ar = ring Ω) S5(Ar = ring Ψ)

T1 (Ar = ring Σ) T2 (Ar = ring Δ) T3 (Ar = ring Φ) T4 (Ar = ring Ω) T5(Ar = ring Ψ)

U1 (Ar = ring Σ) U2 (Ar = ring Δ) U3 (Ar = ring Φ) U4 (Ar = ring Ω) U5(Ar = ring Ψ)

V1 (Ar = ring Σ) V2 (Ar = ring Δ) V3 (Ar = ring Φ) V4 (Ar = ring Ω) V5(Ar = ring Ψ)

W1 (Ar = ring Σ) W2 (Ar = ring Δ) W3 (Ar = ring Φ) W4 (Ar = ring Ω) W5(Ar = ring Ψ)

X1 (Ar = ring Σ) X2 (Ar = ring Δ) X3 (Ar = ring Φ) X4 (Ar = ring Ω) X5(Ar = ring Ψ)

Ex # R^(b′) R^(3′)  1 Me H  2 3-picolyl H  3 aminocarbonylmethyl H  4 Memethyl  5 3-picolyl methyl  6 aminocarbonylmethyl methyl  7 Me ethyl  83-picolyl ethyl  9 aminocarbonylmethyl ethyl  10 Me isopropyl  113-picolyl isopropyl  12 aminocarbonylmethyl isopropyl  13 Me phenyl  143-picolyl phenyl  15 aminocarbonylmethyl phenyl  16 Me benzyl  173-picolyl benzyl  18 aminocarbonylmethyl benzyl  19 Me 2-phenylethyl  203-picolyl 2-phenylethyl  21 aminocarbonylmethyl 2-phenylethyl  22 Me2-(2-methylphenyl)ethyl  23 3-picolyl 2-(2-methylphenyl)ethyl  24aminocarbonylmethyl 2-(2-methylphenyl)ethyl  25 Me2-(3-methylphenyl)ethyl  26 3-picolyl 2-(3-methylphenyl)ethyl  27aminocarbonylmethyl 2-(3-methylphenyl)ethyl  28 Me2-(2,6-dimethylphenyl)ethyl  29 3-picolyl 2-(2,6-dimethylphenyl)ethyl 30 aminocarbonylmethyl 2-(2,6-dimethylphenyl)ethyl  31 Me2-(3,5-dimethylphenyl)ethyl  32 3-picolyl 2-(3,5-dimethylphenyl)ethyl 33 aminocarbonylmethyl 2-(3,5-dimethylphenyl)ethyl  34 Me2-(3-amino-5-methylphenyl)ethyl  35 3-picolyl2-(3-amino-5-methylphenyl)ethyl  36 aminocarbonylmethyl2-(3-amino-5-methylphenyl)ethyl  37 Me 2-(pyridin-4-yl)ethyl  383-picolyl 2-(pyridin-4-yl)ethyl  39 aminocarbonylmethyl2-(pyridin-4-yl)ethyl  40 Me 2-(2,6-dimethylpyridin-4-yl)ethyl  413-picolyl 2-(2,6-dimethylpyridin-4-yl)ethyl  42 aminocarbonylmethyl2-(2,6-dimethylpyridin-4-yl)ethyl  43 Me2-(3,5-dimethylpyridin-4-yl)ethyl  44 3-picolyl2-(3,5-dimethylpyridin-4-yl)ethyl  45 aminocarbonylmethyl2-(3,5-dimethylpyridin-4-yl)ethyl  46 Me styryl  47 3-picolyl styryl  48aminocarbonylmethyl styryl  49 Me hydroxy  50 3-picolyl hydroxy  51aminocarbonylmethyl hydroxy  52 Me methoxy  53 3-picolyl methoxy  54aminocarbonylmethyl methoxy  55 Me ethoxy  56 3-picolyl ethoxy  57aminocarbonylmethyl ethoxy  58 Me isopropyloxy  59 3-picolylisopropyloxy  60 aminocarbonylmethyl isopropyloxy  61 Me tert-butoxy  623-picolyl tert-butoxy  63 aminocarbonylmethyl tert-butoxy  64 Mecyclohexyloxy  65 3-picolyl cyclohexyloxy  66 aminocarbonylmethylcyclohexyloxy  67 Me phenoxy  68 3-picolyl phenoxy  69aminocarbonylmethyl phenoxy  70 Me o-methylphenoxy  71 3-picolylo-methylphenoxy  72 aminocarbonylmethyl o-methylphenoxy  73 Mem-methylphenoxy  74 3-picolyl m-methylphenoxy  75 aminocarbonylmethylm-methylphenoxy  76 Me cinnamyloxy  77 3-picolyl cinnamyloxy  78aminocarbonylmethyl cinnamyloxy  79 Me benzyloxy  80 3-picolyl benzyloxy 81 aminocarbonylmethyl benzyloxy  82 Me phenoxymethyl  83 3-picolylphenoxymethyl  84 aminocarbonylmethyl phenoxymethyl  85 Meo-methylbenzyloxy  86 3-picolyl o-methylbenzyloxy  87aminocarbonylmethyl o-methylbenzyloxy  88 Me m-methylbenzyloxy  893-picolyl m-methylbenzyloxy  90 aminocarbonylmethyl m-methylbenzyloxy 91 Me o,o-dimethylbenzyloxy  92 3-picolyl o,o-dimethylbenzyloxy  93aminocarbonylmethyl o,o-dimethylbenzyloxy  94 Me(2,6-dimethylphenoxy)methyl  95 3-picolyl (2,6-dimethylphenoxy)methyl 96 aminocarbonylmethyl (2,6-dimethylphenoxy)methyl  97 Mem,m-dimethylbenzyloxy  98 3-picolyl m,m-dimethylbenzyloxy  99aminocarbonylmethyl m,m-dimethylbenzyloxy 100 Me(3,5-dimethylphenoxy)methyl 101 3-picolyl (3,5-dimethylphenoxy)methyl102 aminocarbonylmethyl (3,5-dimethylphenoxy)methyl 103 Meo,o-dicyanobenzyloxy 104 3-picolyl o,o-dicyanobenzyloxy 105aminocarbonylmethyl o,o-dicyanobenzyloxy 106 Me m,m-dicyanobenzyloxy 1073-picolyl m,m-dicyanobenzyloxy 108 aminocarbonylmethylm,m-dicyanobenzyloxy 109 Me (2,6-dicyanophenoxy)methyl 110 3-picolyl(2,6-dicyanophenoxy)methyl 111 aminocarbonylmethyl(2,6-dicyanophenoxy)methyl 112 Me (3,5-dicyanophenoxy)methyl 1133-picolyl (3,5-dicyanophenoxy)methyl 114 aminocarbonylmethyl(3,5-dicyanophenoxy)methyl 115 Me o-amino-o-cyanobenzyloxy 116 3-picolylo-amino-o-cyanobenzyloxy 117 aminocarbonylmethylo-amino-o-cyanobenzyloxy 118 Me m-amino-m-cyanobenzyloxy 119 3-picolylm-amino-m-cyanobenzyloxy 120 aminocarbonylmethylm-amino-m-cyanobenzyloxy 121 Me o-amino-o-nitrobenzyloxy 122 3-picolylo-amino-o-nitrobenzyloxy 123 aminocarbonylmethylo-amino-o-nitrobenzyloxy 124 Me m-amino-m-nitrobenzyloxy 125 3-picolylm-amino-m-nitrobenzyloxy 126 aminocarbonylmethylm-amino-m-nitrobenzyloxy 127 Me p-amino-m,m-dimethylbenzyloxy 1283-picolyl p-amino-m,m-dimethylbenzyloxy 129 aminocarbonylmethylp-amino-m,m-dimethylbenzyloxy 130 Me o-amino-o-methylbenzyloxy 1313-picolyl o-amino-o-methylbenzyloxy 132 aminocarbonylmethylo-amino-o-methylbenzyloxy 133 Me m-amino-m-methylbenzyloxy 134 3-picolylm-amino-m-methylbenzyloxy 135 aminocarbonylmethylm-amino-m-methylbenzyloxy 136 Me o-cyano-o-methylbenzyloxy 137 3-picolylo-cyano-o-methylbenzyloxy 138 aminocarbonylmethylo-cyano-o-methylbenzyloxy 139 Me m-cyano-m-methylbenzyloxy 140 3-picolylm-cyano-m-methylbenzyloxy 141 aminocarbonylmethylm-cyano-m-methylbenzyloxy 142 Me o-cyano-o-nitrobenzyloxy 143 3-picolylo-cyano-o-nitrobenzyloxy 144 aminocarbonylmethylo-cyano-o-nitrobenzyloxy 145 Me (2-cyano-6-nitrophenoxy)methyl 1463-picolyl (2-cyano-6-nitrophenoxy)methyl 147 aminocarbonylmethyl(2-cyano-6-nitrophenoxy)methyl 148 Me m-cyano-m-nitrobenzyloxy 1493-picolyl m-cyano-m-nitrobenzyloxy 150 aminocarbonylmethylm-cyano-m-nitrobenzyloxy 151 Me (3-cyano-5-nitrophenoxy)methyl 1523-picolyl (3-cyano-5-nitrophenoxy)methyl 153 aminocarbonylmethyl(3-cyano-5-nitrophenoxy)methyl 154 Me m,m-dimethoxybenzyloxy 1553-picolyl m,m-dimethoxybenzyloxy 156 aminocarbonylmethylm,m-dimethoxybenzyloxy 157 Me m,m-dichlorobenzyloxy 158 3-picolylm,m-dichlorobenzyloxy 159 aminocarbonylmethyl m,m-dichlorobenzyloxy 160Me (3,5-dichlorophenoxy)methyl 161 3-picolyl (3,5-dichlorophenoxy)methyl162 aminocarbonylmethyl (3,5-dichlorophenoxy)methyl 163 Mem,m-dibromobenzyloxy 164 3-picolyl m,m-dibromobenzyloxy 165aminocarbonylmethyl m,m-dibromobenzyloxy 166 Mem,m-bis(trifluoromethyl)benzyloxy 167 3-picolylm,m-bis(trifluoromethyl)benzyloxy 168 aminocarbonylmethylm,m-bis(trifluoromethyl)benzyloxy 169 Me[3,5-bis(trifluoromethyl)phenoxy]methyl 170 3-picolyl[3,5-bis(trifluoromethyl)phenoxy]methyl 171 aminocarbonylmethyl[3,5-bis(trifluoromethyl)phenoxy]methyl 172 Mem-carboxamido-m-methylbenzyloxy 173 3-picolylm-carboxamido-m-methylbenzyloxy 174 aminocarbonylmethylm-carboxamido-m-methylbenzyloxy 175 Me(3-carboxamido-5-methylphenoxy)methyl 176 3-picolyl(3-carboxamido-5-methylphenoxy)methyl 177 aminocarbonylmethyl(3-carboxamido-5-methylphenoxy)methyl 178 Mem-hydroxycarbonyl-m-methylbenzyloxy 179 3-picolylm-hydroxycarbonyl-m-methylbenzyloxy 180 aminocarbonylmethylm-hydroxycarbonyl-m-methylbenzyloxy 181 Me(3-hydroxycarbonyl-5-methylphenoxy)- methyl 182 3-picolyl(3-hydroxycarbonyl-5-methylphenoxy)- methyl 183 aminocarbonylmethyl(3-hydroxycarbonyl-5-methylphenoxy)- methyl 184 Me o-phenylbenzyloxy 1853-picolyl o-phenylbenzyloxy 186 aminocarbonylmethyl o-phenylbenzyloxy187 Me m-phenylbenzyloxy 188 3-picolyl m-phenylbenzyloxy 189aminocarbonylmethyl m-phenylbenzyloxy 190 Me (naphth-1-yl)methoxy 1913-picolyl (naphth-1-yl)methoxy 192 aminocarbonylmethyl(naphth-1-yl)methoxy 193 Me (naphth-2-yl)methoxy 194 3-picolyl(naphth-2-yl)methoxy 195 aminocarbonylmethyl (naphth-2-yl)methoxy 196 Me(2-methylnaphth-1-yl)methoxy 197 3-picolyl (2-methylnaphth-1-yl)methoxy198 aminocarbonylmethyl (2-methylnaphth-1-yl)methoxy 199 Me(4-methylnaphth-2-yl)methoxy 200 3-picolyl (4-methylnaphth-2-yl)methoxy201 aminocarbonylmethyl (4-methylnaphth-2-yl)methoxy 202 Me(pyridin-3-yl)methoxy 203 3-picolyl (pyridin-3-yl)methoxy 204aminocarbonylmethyl (pyridin-3-yl)methoxy 205 Me (pyridin-4-yl)methoxy206 3-picolyl (pyridin-4-yl)methoxy 207 aminocarbonylmethyl(pyridin-4-yl)methoxy 208 Me (3,5-dichloropyridin-4-yl)methoxy 2093-picolyl (3,5-dichloropyridin-4-yl)methoxy 210 aminocarbonylmethyl(3,5-dichloropyridin-4-yl)methoxy 211 Me(3,5-dimethylpyridin-4-yl)methoxy 212 3-picolyl(3,5-dimethylpyridin-4-yl)methoxy 213 aminocarbonylmethyl(3,5-dimethylpyridin-4-yl)methoxy 214 Me(1,2,3-benzotriazol-1-yl)methoxy 215 3-picolyl(1,2,3-benzotriazol-1-yl)methoxy 216 aminocarbonylmethyl(1,2,3-benzotriazol-1-yl)methoxy 217 Me benzhydroxy 218 3-picolylbenzhydroxy 219 aminocarbonylmethyl benzhydroxy 220 Mep-(1,2,3-thiadiazol-5-yl)benzyloxy 221 3-picolylp-(1,2,3-thiadiazol-5-yl)benzyloxy 222 aminocarbonylmethylp-(1,2,3-thiadiazol-5-yl)benzyloxy 223 Me o-(tetrazol-5-yl)benzyloxy 2243-picolyl o-(tetrazol-5-yl)benzyloxy 225 aminocarbonylmethylo-(tetrazol-5-yl)benzyloxy 226 Me m-(tetrazol-5-yl)benzyloxy 2273-picolyl m-(tetrazol-5-yl)benzyloxy 228 aminocarbonylmethylm-(tetrazol-5-yl)benzyloxy 229 Me[3-methyl-5-(tetrazol-5-yl)phenoxy]methyl 230 3-picolyl[3-methyl-5-(tetrazol-5-yl)phenoxy]methyl 231 aminocarbonylmethyl[3-methyl-5-(tetrazol-5-yl)phenoxy]methyl 232 Mem-methyl-m-(tetrazol-5-yl)benzyloxy 233 3-picolylm-methyl-m-(tetrazol-5-yl)benzyloxy 234 aminocarbonylmethylm-methyl-m-(tetrazol-5-yl)benzyloxy 235 Me 2-oxo-2-phenylethoxy 2363-picolyl 2-oxo-2-phenylethoxy 237 aminocarbonylmethyl2-oxo-2-phenylethoxy 238 Me carbo-t-butoxymethoxy 239 3-picolylcarbo-t-butoxymethoxy 240 aminocarbonylmethyl carbo-t-butoxymethoxy 241Me (benzimidazol-2-yl)methoxy 242 3-picolyl (benzimidazol-2-yl)methoxy243 aminocarbonylmethyl (benzimidazol-2-yl)methoxy 244 Me(imidazol-2-yl)methoxy 245 3-picolyl (imidazol-2-yl)methoxy 246aminocarbonylmethyl (imidazol-2-yl)methoxy 247 Me(1,4-dimethylimidazol-5-yl)methoxy 248 3-picolyl(1,4-dimethylimidazol-5-yl)methoxy 249 aminocarbonylmethyl(1,4-dimethylimidazol-5-yl)methoxy 250 Me (thiazol-4-yl)methoxy 2513-picolyl (thiazol-4-yl)methoxy 252 aminocarbonylmethyl(thiazol-4-yl)methoxy 253 Me (quinolin-2-yl)methoxy 254 3-picolyl(quinolin-2-yl)methoxy 255 aminocarbonylmethyl (quinolin-2-yl)methoxy256 Me (1,3-benzodioxo-5-yl)methoxy 257 3-picolyl(1,3-benzodioxo-5-yl)methoxy 258 aminocarbonylmethyl(1,3-benzodioxo-5-yl)methoxy 259 Me (3,5-dimethylisoxazol-4-yl)methoxy260 3-picolyl (3,5-dimethylisoxazol-4-yl)methoxy 261 aminocarbonylmethyl(3,5-dimethylisoxazol-4-yl)methoxy 262 Me(3,5-dimethylpyrazol-1-yl)methoxy 263 3-picolyl(3,5-dimethylpyrazol-1-yl)methoxy 264 aminocarbonylmethyl(3,5-dimethylpyrazol-1-yl)methoxy 265 Me(1,3,5-trimethylpyrazol-4-yl)methoxy 266 3-picolyl(1,3,5-trimethylpyrazol-4-yl)methoxy 267 aminocarbonylmethyl(1,3,5-trimethylpyrazol-4-yl)methoxy 268 Me 4-quinolinylmethoxy 2693-picolyl 4-quinolinylmethoxy 270 aminocarbonylmethyl4-quinolinylmethoxy 271 Me 2-methyl-4-quinolinylmethoxy 272 3-picolyl2-methyl-4-quinolinylmethoxy 273 aminocarbonylmethyl2-methyl-4-quinolinylmethoxy 274 Me 4-quinolinyloxymethyl 275 3-picolyl4-quinolinyloxymethyl 276 aminocarbonylmethyl 4-quinolinyloxymethyl

TABLE 4

A1 (n = 1) A2 (n = 2)

B1 (n = 1) B2 (n = 2)

C1 (n = 1) C2 (n = 2)

D1 (n = 1) D2 (n = 2)

E1 (n = 1) E2 (n = 2)

F1 (n = 1) F2 (n = 2)

G1 (n = 1) G2 (n = 2)

H1 (n = 1) H2 (n = 2)

I1 (n = 1) I2 (n = 2)

J1 (n = 1) J2 (n = 2)

K1 (n = 1) K2 (n = 2)

L1 (n = 1) L2 (n = 2)

M1 (n = 1) M2 (n = 2)

N1 (n = 1) N2 (n = 2)

O1 (n = 1) O2 (n = 2)

P1 (n = 1) P2 (n = 2)

Q1 (n = 1) Q2 (n = 2)

R1 (n = 1) R2 (n = 2)

S1 (n = 1) S2 (n = 2)

T1 (n = 1) T2 (n = 2)

U1 (n = 1) U2 (n = 2)

V1 (n = 1) V2 (n = 2)

W1 (n = 1) W2 (n = 2)

X1 (n = 1) X2 (n = 2) Ex # R^(b′) R^(3′)  1 Me H  2 3-picolyl H  3aminocarbonylmethyl H  4 Me methyl  5 3-picolyl methyl  6aminocarbonylmethyl methyl  7 Me ethyl  8 3-picolyl ethyl  9aminocarbonylmethyl ethyl  10 Me isopropyl  11 3-picolyl isopropyl  12aminocarbonylmethyl isopropyl  13 Me phenyl  14 3-picolyl phenyl  15aminocarbonylmethyl phenyl  16 Me benzyl  17 3-picolyl benzyl  18aminocarbonylmethyl benzyl  19 Me o-methylbenzyl  20 3-picolylo-methylbenzyl  21 aminocarbonylmethyl o-methylbenzyl  22 Mem-methylbenzyl  23 3-picolyl m-methylbenzyl  24 aminocarbonylmethylm-methylbenzyl  25 Me p-methylbenzyl  26 3-picolyl p-methylbenzyl  27aminocarbonylmethyl p-methylbenzyl  28 Me 2-phenylethyl  29 3-picolyl2-phenylethyl  30 aminocarbonylmethyl 2-phenylethyl  31 Me2-(2-methylphenyl)ethyl  32 3-picolyl 2-(2-methylphenyl)ethyl  33aminocarbonylmethyl 2-(2-methylphenyl)ethyl  34 Me2-(3-methylphenyl)ethyl  35 3-picolyl 2-(3-methylphenyl)ethyl  36aminocarbonylmethyl 2-(3-methylphenyl)ethyl  37 Me2-(4-methylphenyl)ethyl  38 3-picolyl 2-(4-methylphenyl)ethyl  39aminocarbonylmethyl 2-(4-methylphenyl)ethyl  40 Me2-(2,6-dimethylphenyl)ethyl  41 3-picolyl 2-(2,6-dimethylphenyl)ethyl 42 aminocarbonylmethyl 2-(2,6-dimethylphenyl)ethyl  43 Meo,o-dimethylbenzyl  44 3-picolyl o,o-dimethylbenzyl  45aminocarbonylmethyl o,o-dimethylbenzyl  46 Me2-(3,5-dimethylphenyl)ethyl  47 3-picolyl 2-(3,5-dimethylphenyl)ethyl 48 aminocarbonylmethyl 2-(3,5-dimethylphenyl)ethyl  49 Mem,m-dimethylbenzyl  50 3-picolyl m,m-dimethylbenzyl  51aminocarbonylmethyl m,m-dimethylbenzyl  52 Me2-(2-amino-6-methylphenyl)ethyl  53 3-picolyl2-(2-amino-6-methylphenyl)ethyl  54 aminocarbonylmethyl2-(2-amino-6-methylphenyl)ethyl  55 Me o-amino-o-methylbenzyl  563-picolyl o-amino-o-methylbenzyl  57 aminocarbonylmethylo-amino-o-methylbenzyl  58 Me 2-(3-amino-5-methylphenyl)ethyl  593-picolyl 2-(3-amino-5-methylphenyl)ethyl  60 aminocarbonylmethyl2-(3-amino-5-methylphenyl)ethyl  61 Me m-amino-m-methylbenzyl  623-picolyl m-amino-m-methylbenzyl  63 aminocarbonylmethylm-amino-m-methylbenzyl  64 Me 2-(pyridin-2-yl)ethyl  65 3-picolyl2-(pyridin-2-yl)ethyl  66 aminocarbonylmethyl 2-(pyridin-2-yl)ethyl  67Me (pyridin-2-yl)methyl  68 3-picolyl (pyridin-2-yl)methyl  69aminocarbonylmethyl (pyridin-2-yl)methyl  70 Me 2-(pyridin-3-yl)ethyl 71 3-picolyl 2-(pyridin-3-yl)ethyl  72 aminocarbonylmethyl2-(pyridin-3-yl)ethyl  73 Me (pyridin-3-yl)methyl  74 3-picolyl(pyridin-3-yl)methyl  75 aminocarbonylmethyl (pyridin-3-yl)methyl  76 Me2-(pyridin-4-yl)ethyl  77 3-picolyl 2-(pyridin-4-yl)ethyl  78aminocarbonylmethyl 2-(pyridin-4-yl)ethyl  79 Me (pyridin-4-yl)methyl 80 3-picolyl (pyridin-4-yl)methyl  81 aminocarbonylmethyl(pyridin-4-yl)methyl  82 Me 2-(2,6-dimethylpyridin-4-yl)ethyl  833-picolyl 2-(2,6-dimethylpyridin-4-yl)ethyl  84 aminocarbonylmethyl2-(2,6-dimethylpyridin-4-yl)ethyl  85 Me(2,6-dimethylpyridin-4-yl)methyl  86 3-picolyl(2,6-dimethylpyridin-4-yl)methyl  87 aminocarbonylmethyl(2,6-dimethylpyridin-4-yl)methyl  88 Me2-(3,5-dimethylpyridin-4-yl)ethyl  89 3-picolyl2-(3,5-dimethylpyridin-4-yl)ethyl  90 aminocarbonylmethyl2-(3,5-dimethylpyridin-4-yl)ethyl  91 Me(3,5-dimethylpyridin-4-yl)methyl  92 3-picolyl(3,5-dimethylpyridin-4-yl)methyl  93 aminocarbonylmethyl(3,5-dimethylpyridin-4-yl)methyl  94 Me styryl  95 3-picolyl styryl  96aminocarbonylmethyl styryl  97 Me cyclohexylmethyl  98 3-picolylcyclohexylmethyl  99 aminocarbonylmethyl cyclohexylmethyl 100 Mephenoxymethyl 101 3-picolyl phenoxymethyl 102 aminocarbonylmethylphenoxymethyl 103 Me (2,6-dimethylphenoxy)methyl 104 3-picolyl(2,6-dimethylphenoxy)methyl 105 aminocarbonylmethyl(2,6-dimethylphenoxy)methyl 106 Me (3,5-dimethylphenoxy)methyl 1073-picolyl (3,5-dimethylphenoxy)methyl 108 aminocarbonylmethyl(3,5-dimethylphenoxy)methyl 109 Me (2,6-dicyanophenoxy)methyl 1103-picolyl (2,6-dicyanophenoxy)methyl 111 aminocarbonylmethyl(2,6-dicyanophenoxy)methyl 112 Me (3,5-dicyanophenoxy)methyl 1133-picolyl (3,5-dicyanophenoxy)methyl 114 aminocarbonylmethyl(3,5-dicyanophenoxy)methyl 115 Me 2-(2-amino-6-cyanophenyl)ethyl 1163-picolyl 2-(2-amino-6-cyanophenyl)ethyl 117 aminocarbonylmethyl2-(2-amino-6-cyanophenyl)ethyl 118 Me o-amino-o-cyanobenzyl 1193-picolyl o-amino-o-cyanobenzyl 120 aminocarbonylmethylo-amino-o-cyanobenzyl 121 Me 2-(3-amino-5-cyanophenyl)ethyl 1223-picolyl 2-(3-amino-5-cyanophenyl)ethyl 123 aminocarbonylmethyl2-(3-amino-5-cyanophenyl)ethyl 124 Me m-amino-m-cyanobenzyl 1253-picolyl m-amino-m-cyanobenzyl 126 aminocarbonylmethylm-amino-m-cyanobenzyl 127 Me 2-(2-amino-6-nitrophenyl)ethyl 1283-picolyl 2-(2-amino-6-nitrophenyl)ethyl 129 aminocarbonylmethyl2-(2-amino-6-nitrophenyl)ethyl 130 Me o-amino-o-nitrobenzyl 1313-picolyl o-amino-o-nitrobenzyl 132 aminocarbonylmethylo-amino-o-nitrobenzyl 133 Me 2-(3-amino-5-nitrophenyl)ethyl 1343-picolyl 2-(3-amino-5-nitrophenyl)ethyl 135 aminocarbonylmethyl2-(3-amino-5-nitrophenyl)ethyl 136 Me m-amino-m-nitrobenzyl 1373-picolyl m-amino-m-nitrobenzyl 138 aminocarbonylmethylm-amino-m-nitrobenzyl 139 Me 2-(4-amino-2,6-dimethylphenyl)ethyl 1403-picolyl 2-(4-amino-2,6-dimethylphenyl)ethyl 141 aminocarbonylmethyl2-(4-amino-2,6-dimethylphenyl)ethyl 142 Me p-amino-o,o-dimethylbenzyl143 3-picolyl p-amino-o,o-dimethylbenzyl 144 aminocarbonylmethylp-amino-o,o-dimethylbenzyl 145 Me 2-(4-amino-3,5-dimethylphenyl)ethyl146 3-picolyl 2-(4-amino-3,5-dimethylphenyl)ethyl 147aminocarbonylmethyl 2-(4-amino-3,5-dimethylphenyl)ethyl 148 Mep-amino-m,m-dimethylbenzyl 149 3-picolyl p-amino-m,m-dimethylbenzyl 150aminocarbonylmethyl p-amino-m,m-dimethylbenzyl 151 Me2-(2-cyano-6-methylphenyl)ethyl 152 3-picolyl2-(2-cyano-6-methylphenyl)ethyl 153 aminocarbonylmethyl2-(2-cyano-6-methylphenyl)ethyl 154 Me o-cyano-o-methylbenzyl 1553-picolyl o-cyano-o-methylbenzyl 156 aminocarbonylmethylo-cyano-o-methylbenzyl 157 Me 2-(3-cyano-5-methylphenyl)ethyl 1583-picolyl 2-(3-cyano-5-methylphenyl)ethyl 159 aminocarbonylmethyl2-(3-cyano-5-methylphenyl)ethyl 160 Me m-cyano-m-methylbenzyl 1613-picolyl m-cyano-m-methylbenzyl 162 aminocarbonylmethylm-cyano-m-methylbenzyl 163 Me 2-(2-cyano-6-nitrophenyl)ethyl 1643-picolyl 2-(2-cyano-6-nitrophenyl)ethyl 165 aminocarbonylmethyl2-(2-cyano-6-nitrophenyl)ethyl 166 Me o-cyano-o-nitrobenzyl 1673-picolyl o-cyano-o-nitrobenzyl 168 aminocarbonylmethylo-cyano-o-nitrobenzyl 169 Me (2-cyano-6-nitrophenoxy)methyl 1703-picolyl (2-cyano-6-nitrophenoxy)methyl 171 aminocarbonylmethyl(2-cyano-6-nitrophenoxy)methyl 172 Me 2-(3-cyano-5-nitrophenyl)ethyl 1733-picolyl 2-(3-cyano-5-nitrophenyl)ethyl 174 aminocarbonylmethyl2-(3-cyano-5-nitrophenyl)ethyl 175 Me m-cyano-m-nitrobenzyl 1763-picolyl m-cyano-m-nitrobenzyl 177 aminocarbonylmethylm-cyano-m-nitrobenzyl 178 Me (3-cyano-5-nitrophenoxy)methyl 1793-picolyl (3-cyano-5-nitrophenoxy)methyl 180 aminocarbonylmethyl(3-cyano-5-nitrophenoxy)methyl 181 Me 2-(3,5-dimethoxyphenyl)ethyl 1823-picolyl 2-(3,5-dimethoxyphenyl)ethyl 183 aminocarbonylmethyl2-(3,5-dimethoxyphenyl)ethyl 184 Me m,m-dimethoxybenzyl 185 3-picolylm,m-dimethoxybenzyl 186 aminocarbonylmethyl m,m-dimethoxybenzyl 187 Me2-(3,5-dichlorophenyl)ethyl 188 3-picolyl 2-(3,5-dichlorophenyl)ethyl189 aminocarbonylmethyl 2-(3,5-dichlorophenyl)ethyl 190 Mem,m-dichlorobenzyl 191 3-picolyl m,m-dichlorobenzyl 192aminocarbonylmethyl m,m-dichlorobenzyl 193 Me(3,5-dichlorophenoxy)methyl 194 3-picolyl (3,5-dichlorophenoxy)methyl195 aminocarbonylmethyl (3,5-dichlorophenoxy)methyl 196 Me2-(3,5-dibromophenyl)ethyl 197 3-picolyl 2-(3,5-dibromophenyl)ethyl 198aminocarbonylmethyl 2-(3,5-dibromophenyl)ethyl 199 Me m,m-dibromobenzyl200 3-picolyl m,m-dibromobenzyl 201 aminocarbonylmethylm,m-dibromobenzyl 202 Me 2-[3,5-bis(trifluoromethyl)phenyl]ethyl 2033-picolyl 2-[3,5-bis(trifluoromethyl)phenyl]ethyl 204aminocarbonylmethyl 2-[3,5-bis(trifluoromethyl)phenyl]ethyl 205 Me3,5-bis(trifluoromethyl)phenylmethyl 206 3-picolyl3,5-bis(trifluoromethyl)phenylmethyl 207 aminocarbonylmethyl3,5-bis(trifluoromethyl)phenylmethyl 208 Me[3,5-bis(trifluoromethyl)phenoxy]methyl 209 3-picolyl[3,5-bis(trifluoromethyl)phenoxy]methyl 210 aminocarbonylmethyl[3,5-bis(trifluoromethyl)phenoxy]methyl 211 Me2-(3-carboxamido-5-methylphenyl)ethyl 212 3-picolyl2-(3-carboxamido-5-methylphenyl)ethyl 213 aminocarbonylmethyl2-(3-carboxamido-5-methylphenyl)ethyl 214 Mem-carboxamido-m-methylbenzyl 215 3-picolyl m-carboxamido-m-methylbenzyl216 aminocarbonylmethyl m-carboxamido-m-methylbenzyl 217 Me(3-carboxamido-5-methylphenoxy)methyl 218 3-picolyl(3-carboxamido-5-methylphenoxy)methyl 219 aminocarbonylmethyl(3-carboxamido-5-methylphenoxy)methyl 220 Me2-(3-hydroxycarbonyl-5-methylphenyl)- ethyl 221 3-picolyl2-(3-hydroxycarbonyl-5-methylphenyl)- ethyl 222 aminocarbonylmethyl2-(3-hydroxycarbonyl-5-methylphenyl)- ethyl 223 Mem-hydroxycarbonyl-m-methylbenzyl 224 3-picolylm-hydroxycarbonyl-m-methylbenzyl 225 aminocarbonylmethylm-hydroxycarbonyl-m-methylbenzyl 226 Me(3-hydroxycarbonyl-5-methylphenoxy)- methyl 227 3-picolyl(3-hydroxycarbonyl-5-methylphenoxy)- methyl 228 aminocarbonylmethyl(3-hydroxycarbonyl-5-methylphenoxy)- methyl 229 Me2-(2-phenylphenyl)ethyl 230 3-picolyl 2-(2-phenylphenyl)ethyl 231aminocarbonylmethyl 2-(2-phenylphenyl)ethyl 232 Me o-phenylbenzyl 2333-picolyl o-phenylbenzyl 234 aminocarbonylmethyl o-phenylbenzyl 235 Me2-(3-phenylphenyl)ethyl 236 3-picolyl 2-(3-phenylphenyl)ethyl 237aminocarbonylmethyl 2-(3-phenylphenyl)ethyl 238 Me m-phenylbenzyl 2393-picolyl m-phenylbenzyl 240 aminocarbonylmethyl m-phenylbenzyl 241 Me2-(naphth-1-yl)ethyl 242 3-picolyl 2-(naphth-1-yl)ethyl 243aminocarbonylmethyl 2-(naphth-1-yl)ethyl 244 Me (naphth-1-yl)methyl 2453-picolyl (naphth-1-yl)methyl 246 aminocarbonylmethyl(naphth-1-yl)methyl 247 Me 2-(naphth-2-yl)ethyl 248 3-picolyl2-(naphth-2-yl)ethyl 249 aminocarbonylmethyl 2-(naphth-2-yl)ethyl 250 Me(naphth-2-yl)methyl 251 3-picolyl (naphth-2-yl)methyl 252aminocarbonylmethyl (naphth-2-yl)methyl 253 Me2-(2-methylnaphth-1-yl)ethyl 254 3-picolyl 2-(2-methylnaphth-1-yl)ethyl255 aminocarbonylmethyl 2-(2-methylnaphth-1-yl)ethyl 256 Me(2-methylnaphth-1-yl)methyl 257 3-picolyl (2-methylnaphth-1-yl)methyl258 aminocarbonylmethyl (2-methylnaphth-1-yl)methyl 259 Me2-(4-methylnaphth-2-yl)ethyl 260 3-picolyl 2-(4-methylnaphth-2-yl)ethyl261 aminocarbonylmethyl 2-(4-methylnaphth-2-yl)ethyl 262 Me(4-methylnaphth-2-yl)methyl 263 3-picolyl (4-methylnaphth-2-yl)methyl264 aminocarbonylmethyl (4-methylnaphth-2-yl)methyl 265 Me2-(3,5-dichloropyridin-4-yl)ethyl 266 3-picolyl2-(3,5-dichloropyridin-4-yl)ethyl 267 aminocarbonylmethyl2-(3,5-dichloropyridin-4-yl)ethyl 268 Me(3,5-dichloropyridin-4-yl)methyl 269 3-picolyl(3,5-dichloropyridin-4-yl)methyl 270 aminocarbonylmethyl(3,5-dichloropyridin-4-yl)methyl 271 Me 2-(1,2,3-benzotriazol-1-yl)ethyl272 3-picolyl 2-(1,2,3-benzotriazol-1-yl)ethyl 273 aminocarbonylmethyl2-(1,2,3-benzotriazol-1-yl)ethyl 274 Me2-[4-(1,2,3-thiadiazol-5-yl)phenyl]ethyl 275 3-picolyl2-[4-(1,2,3-thiadiazol-5-yl)phenyl]ethyl 276 aminocarbonylmethyl2-[4-(1,2,3-thiadiazol-5-yl)phenyl]ethyl 277 Me4-(1,2,3-thiadiazol-5-yl)phenylmethyl 278 3-picolyl4-(1,2,3-thiadiazol-5-yl)phenylmethyl 279 aminocarbonylmethyl4-(1,2,3-thiadiazol-5-yl)phenylmethyl 280 Me2-[2-(tetrazol-5-yl)phenyl]ethyl 281 3-picolyl2-[2-(tetrazol-5-yl)phenyl]ethyl 282 aminocarbonylmethyl2-[2-(tetrazol-5-yl)phenyl]ethyl 283 Me 2-(tetrazol-5-yl)phenylmethyl284 3-picolyl 2-(tetrazol-5-yl)phenylmethyl 285 aminocarbonylmethyl2-(tetrazol-5-yl)phenylmethyl 286 Me 2-[3-(tetrazol-5-yl)phenyl]ethyl287 3-picolyl 2-[3-(tetrazol-5-yl)phenyl]ethyl 288 aminocarbonylmethyl2-[3-(tetrazol-5-yl)phenyl]ethyl 289 Me 3-(tetrazol-5-yl)phenylmethyl290 3-picolyl 3-(tetrazol-5-yl)phenylmethyl 291 aminocarbonylmethyl3-(tetrazol-5-yl)phenylmethyl 292 Me[3-methyl-5-(tetrazol-5-yl)phenoxy]methyl 293 3-picolyl[3-methyl-5-(tetrazol-5-yl)phenoxy]methyl 294 aminocarbonylmethyl[3-methyl-5-(tetrazol-5-yl)phenoxy]methyl 295 Me2-[3-methyl-5-(tetrazol-5-yl)phenyl]ethyl 296 3-picolyl2-[3-methyl-5-(tetrazol-5-yl)phenyl]ethyl 297 aminocarbonylmethyl2-[3-methyl-5-(tetrazol-5-yl)phenyl]ethyl 298 Me3-methyl-5-(tetrazol-5-yl)phenylmethyl 299 3-picolyl3-methyl-5-(tetrazol-5-yl)phenylmethyl 300 aminocarbonylmethyl3-methyl-5-(tetrazol-5-yl)phenylmethyl 301 Me 2-(benzimidazol-2-yl)ethyl302 3-picolyl 2-(benzimidazol-2-yl)ethyl 302 aminocarbonylmethyl2-(benzimidazol-2-yl)ethyl 304 Me (benzimidazol-2-yl)methyl 3053-picolyl (benzimidazol-2-yl)methyl 306 aminocarbonylmethyl(benzimidazol-2-yl)methyl 307 Me 2-(imidazol-2-yl)ethyl 308 3-picolyl2-(imidazol-2-yl)ethyl 309 aminocarbonylmethyl 2-(imidazol-2-yl)ethyl310 Me (imidazol-2-yl)methyl 311 3-picolyl (imidazol-2-yl)methyl 312aminocarbonylmethyl (imidazol-2-yl)methyl 313 Me2-(1,4-dimethylimidazol-5-yl)ethyl 314 3-picolyl2-(1,4-dimethylimidazol-5-yl)ethyl 315 aminocarbonylmethyl2-(1,4-dimethylimidazol-5-yl)ethyl 316 Me(1,4-dimethylimidazol-5-yl)methyl 317 3-picolyl(1,4-dimethylimidazol-5-yl)methyl 318 aminocarbonylmethyl(1,4-dimethylimidazol-5-yl)methyl 319 Me 2-(thiazol-4-yl)ethyl 3203-picolyl 2-(thiazol-4-yl)ethyl 321 aminocarbonylmethyl2-(thiazol-4-yl)ethyl 322 Me (thiazol-4-yl)methyl 323 3-picolyl(thiazol-4-yl)methyl 324 aminocarbonylmethyl (thiazol-4-yl)methyl 325 Me2-(quinolin-2-yl)ethyl 326 3-picolyl 2-(quinolin-2-yl)ethyl 327aminocarbonylmethyl 2-(quinolin-2-yl)ethyl 328 Me (quinolin-2-yl)methyl329 3-picolyl (quinolin-2-yl)methyl 330 aminocarbonylmethyl(quinolin-2-yl)methy1 331 Me 2-(1,3-benzodioxo-5-yl)ethyl 332 3-picolyl2-(1,3-benzodioxo-5-yl)ethyl 333 aminocarbonylmethyl2-(1,3-benzodioxo-5-yl)ethyl 334 Me (1,3-benzodioxo-5-yl)methyl 3353-picolyl (1,3-benzodioxo-5-yl)methyl 336 aminocarbonylmethyl(1,3-benzodioxo-5-yl)methyl 337 Me 2-(3,5-dimethylisoxazol-4-yl)ethyl338 3-picolyl 2-(3,5-dimethylisoxazol-4-yl)ethyl 339 aminocarbonylmethyl2-(3,5-dimethylisoxazol-4-yl)ethyl 340 Me(3,5-dimethylisoxazol-4-yl)methyl 341 3-picolyl(3,5-dimethylisoxazol-4-yl)methyl 342 aminocarbonylmethyl(3,5-dimethylisoxazol-4-yl)methyl 343 Me2-(3,5-dimethylpyrazol-1-yl)ethyl 344 3-picolyl2-(3,5-dimethylpyrazol-1-yl)ethyl 345 aminocarbonylmethyl2-(3,5-dimethylpyrazol-1-yl)ethyl 346 Me(3,5-dimethylpyrazol-1-yl)methyl 347 3-picolyl(3,5-dimethylpyrazol-1-yl)methyl 348 aminocarbonylmethyl(3,5-dimethylpyrazol-1-yl)methyl 349 Me2-(1,3,5-trimethylpyrazol-4-yl)ethyl 350 3-picolyl2-(1,3,5-trimethylpyrazol-4-yl)ethyl 351 aminocarbonylmethyl2-(1,3,5-trimethylpyrazol-4-yl)ethyl 352 Me(1,3,5-trimethylpyrazol-4-yl)methyl 353 3-picolyl(1,3,5-trimethylpyrazol-4-yl)methyl 354 aminocarbonylmethyl(1,3,5-trimethylpyrazol-4-yl)methyl

TABLE 5

A1 (n = 1) A2 (n = 2)

B1 (n = 1) B2 (n = 2)

C1 (n = 1) C2 (n = 2)

D1 (n = 1) D2 (n = 2)

E1 (n = 1) E2 (n = 2)

F1 (n = 1) F2 (n = 2)

G1 (n = 1) G2 (n = 2)

H1 (n = 1) H2 (n = 2)

I1 (n = 1) I2 (n = 2)

J1 (n = 1) J2 (n = 2)

K1 (n = 1) K2 (n = 2)

L1 (n = 1) L2 (n = 2)

M1 (n = 1) M2 (n = 2)

N1 (n = 1) N2 (n = 2)

O1 (n = 1) O2 (n = 2)

P1 (n = 1) P2 (n = 2)

Q1 (n = 1) Q2 (n = 2)

R1 (n = 1) R2 (n = 2)

S1 (n = 1) S2 (n = 2)

T1 (n = 1) T2 (n = 2)

U1 (n = 1) U2 (n = 2)

V1 (n = 1) V2 (n = 2)

W1 (n = 1) W2 (n = 2)

X1 (n = 1) X2 (n = 2) Ex# R^(b’) R^(3’) 1 Me H 2 3-picolyl H 3aminocarbonylmethyl H 4 Me methyl 5 3-picolyl methyl 6aminocarbonylmethyl methyl 7 Me ethyl 8 3-picolyl ethyl 9aminocarbonylmethyl ethyl 10 Me isopropyl 11 3-picolyl isopropyl 12aminocarbonylmethyl isopropyl 13 Me phenyl 14 3-picolyl phenyl 15aminocarbonylmethyl phenyl 16 Me benzyl 17 3-picolyl benzyl 18aminocarbonylmethyl benzyl 19 Me 2-phenylethyl 20 3-picolyl2-phenylethyl 21 aminocarbonylmethyl 2-phenylethyl 22 Me2-(2-methylphenyl)ethyl 23 3-picolyl 2-(2-methylphenyl)ethyl 24aminocarbonylmethyl 2-(2-methylphenyl)ethyl 25 Me2-(3-methylphenyl)ethyl 26 3-picolyl 2-(3-methylphenyl)ethyl 27aminocarbonylmethyl 2-(3-methylphenyl)ethyl 28 Me2-(2,6-dimethylphenyl)ethyl 29 3-picolyl 2-(2,6-dimethylphenyl)ethyl 30aminocarbonylmethyl 2-(2,6-dimethylphenyl)ethyl 31 Me2-(3,5-dimethylphenyl)ethyl 32 3-picolyl 2-(3,5-dimethylphenyl)ethyl 33aminocarbonylmethyl 2-(3,5-dimethylphenyl)ethyl 34 Me2-(3-amino-5-methylphenyl)ethyl 35 3-picolyl2-(3-amino-5-methylphenyl)ethyl 36 aminocarbonylmethyl2-(3-amino-5-methylphenyl)ethyl 37 Me 2-(pyridin-4-yl)ethyl 38 3-picolyl2-(pyridin-4-yl)ethyl 39 aminocarbonylmethyl 2-(pyridin-4-yl)ethyl 40 Me2-(2,6-dimethylpyridin-4-yl)ethyl 41 3-picolyl2-(2,6-dimethylpyridin-4-yl)ethyl 42 aminocarbonylmethyl2-(2,6-dimethylpyridin-4-yl)ethyl 43 Me2-(3,5-dimethylpyridin-4-yl)ethyl 44 3-picolyl2-(3,5-dimethylpyridin-4-yl)ethyl 45 aminocarbonylmethyl2-(3,5-dimethylpyridin-4-yl)ethyl 46 Me styryl 47 3-picolyl styryl 48aminocarbonylmethyl styryl 49 Me hydroxy 50 3-picolyl hydroxy 51aminocarbonylmethyl hydroxy 52 Me methoxy 53 3-picolyl methoxy 54aminocarbonylmethyl methoxy 55 Me ethoxy 56 3-picolyl ethoxy 57aminocarbonylmethyl ethoxy 58 Me isopropyloxy 59 3-picolyl isopropyloxy60 aminocarbonylmethyl isopropyloxy 61 Me tert-butoxy 62 3-picolyltert-butoxy 63 aminocarbonylmethyl tert-butoxy 64 Me cyclohexyloxy 653-picolyl cyclohexyloxy 66 aminocarbonylmethyl cyclohexyloxy 67 Mephenoxy 68 3-picolyl phenoxy 69 aminocarbonylmethyl phenoxy 70 Meo-methylphenoxy 71 3-picolyl o-methylphenoxy 72 aminocarbonylmethylo-methylphenoxy 73 Me m-methylphenoxy 74 3-picolyl m-methylphenoxy 75aminocarbonylmethyl m-methylphenoxy 76 Me cinnamyloxy 77 3-picolylcinnamyloxy 78 aminocarbonylmethyl cinnamyloxy 79 Me benzyloxy 803-picolyl benzyloxy 81 aminocarbonylmethyl benzyloxy 82 Me phenoxymethyl83 3-picolyl phenoxymethyl 84 aminocarbonylmethyl phenoxymethyl 85 Meo-methylbenzyloxy 86 3-picolyl o-methylbenzyloxy 87 aminocarbonylmethylo-methylbenzyloxy 88 Me m-methylbenzyloxy 89 3-picolyl m-methylbenzyloxy90 aminocarbonylmethyl m-methylbenzyloxy 91 Me o,o-dimethylbenzyloxy 923-picolyl o,o-dimethylbenzyloxy 93 aminocarbonylmethylo,o-dimethylbenzyloxy 94 Me (2,6-dimethylphenoxy)methyl 95 3-picolyl(2,6-dimethylphenoxy)methyl 96 aminocarbonylmethyl(2,6-dimethylphenoxy)methyl 97 Me m,m-dimethylbenzyloxy 98 3-picolylm,m-dimethylbenzyloxy 99 aminocarbonylmethyl m,m-dimethylbenzyloxy 100Me (3,5-dimethylphenoxy)methyl 101 3-picolyl (3,5-dimethylphenoxy)methyl102 aminocarbonylmethyl (3,5-dimethylphenoxy)methyl 103 Meo,o-dicyanobenzyloxy 104 3-picolyl o,o-dicyanobenzyloxy 105aminocarbonylmethyl o,o-dicyanobenzyloxy 106 Me m,m-dicyanobenzyloxy 1073-picolyl m,m-dicyanobenzyloxy 108 aminocarbonylmethylm,m-dicyanobenzyloxy 109 Me (2,6-dicyanophenoxy)methyl 110 3-picolyl(2,6-dicyanophenoxy)methyl 111 aminocarbonylmethyl(2,6-dicyanophenoxy)methyl 112 Me (3,5-dicyanophenoxy)methyl 1133-picolyl (3,5-dicyanophenoxy)methyl 114 aminocarbonylmethyl(3,5-dicyanophenoxy)methyl 115 Me o-amino-o-cyanobenzyloxy 116 3-picolylo-amino-o-cyanobenzyloxy 117 aminocarbonylmethylo-amino-o-cyanobenzyloxy 118 Me m-amino-m-cyanobenzyloxy 119 3-picolylm-amino-m-cyanobenzyloxy 120 aminocarbonylmethylm-amino-m-cyanobenzyloxy 121 Me o-amino-o-nitrobenzyloxy 122 3-picolylo-amino-o-nitrobenzyloxy 123 aminocarbonylmethylo-amino-o-nitrobenzyloxy 124 Me m-amino-m-nitrobenzyloxy 125 3-picolylm-amino-m-nitrobenzyloxy 126 aminocarbonylmethylm-amino-m-nitrobenzyloxy 127 Me p-amino-m,m-dimethylbenzyloxy 1283-picolyl p-amino-m,m-dimethylbenzyloxy 129 aminocarbonylmethylp-amino-m,m-dimethylbenzyloxy 130 Me o-amino-o-methylbenzyloxy 1313-picolyl o-amino-o-methylbenzyloxy 132 aminocarbonylmethylo-amino-o-methylbenzyloxy 133 Me m-amino-m-methylbenzyloxy 134 3-picolylm-amino-m-methylbenzyloxy 135 aminocarbonylmethylm-amino-m-methylbenzyloxy 136 Me o-cyano-o-methylbenzyloxy 137 3-picolylo-cyano-o-methylbenzyloxy 138 aminocarbonylmethylo-cyano-o-methylbenzyloxy 139 Me m-cyano-m-methylbenzyloxy 140 3-picolylm-cyano-m-methylbenzyloxy 141 aminocarbonylmethylm-cyano-m-methylbenzyloxy 142 Me o-cyano-o-nitrobenzyloxy 143 3-picolylo-cyano-o-nitrobenzyloxy 144 aminocarbonylmethylo-cyano-o-nitrobenzyloxy 145 Me (2-cyano-6-nitrophenoxy)methyl 1463-picolyl (2-cyano-6-nitrophenoxy)methyl 147 aminocarbonylmethyl(2-cyano-6-nitrophenoxy)methyl 148 Me m-cyano-m-nitrobenzyloxy 1493-picolyl m-cyano-m-nitrobenzyloxy 150 aminocarbonylmethylm-cyano-m-nitrobenzyloxy 151 Me (3-cyano-5-nitrophenoxy)methyl 1523-picolyl (3-cyano-5-nitrophenoxy)methyl 153 aminocarbonylmethyl(3-cyano-5-nitrophenoxy)methyl 154 Me m,m-dimethoxybenzyloxy 1553-picolyl m,m-dimethoxybenzyloxy 156 aminocarbonylmethylm,m-dimethoxybenzyloxy 157 Me m,m-dichlorobenzyloxy 158 3-picolylm,m-dichlorobenzyloxy 159 aminocarbonylmethyl m,m-dichlorobenzyloxy 160Me (3,5-dichlorophenoxy)methyl 161 3-picolyl (3,5-dichlorophenoxy)methyl162 aminocarbonylmethyl (3,5-dichlorophenoxy)methyl 163 Mem,m-dibromobenzyloxy 164 3-picolyl m,m-dibromobenzyloxy 165aminocarbonylmethyl m,m-dibromobenzyloxy 166 Mem,m-bis(trifluoromethyl)benzyloxy 167 3-picolylm,m-bis(trifluoromethyl)benzyloxy 168 aminocarbonylmethylm,m-bis(trifluoromethyl)benzyloxy 169 Me[3,5-bis(trifluoromethyl)phenoxy]methyl 170 3-picolyl[3,5-bis(trifluoromethyl)phenoxy]methyl 171 aminocarbonylmethyl[3,5-bis(trifluoromethyl)phenoxy]methyl 172 Mem-carboxamido-m-methylbenzyloxy 173 3-picolylm-carboxamido-m-methylbenzyloxy 174 aminocarbonylmethylm-carboxamido-m-methylbenzyloxy 175 Me(3-carboxamido-5-methylphenoxy)methyl 176 3-picolyl(3-carboxamido-5-methylphenoxy)methyl 177 aminocarbonylmethyl(3-carboxamido-5-methylphenoxy)methyl 178 Mem-hydroxycarbonyl-m-methylbenzyloxy 179 3-picolylm-hydroxycarbonyl-m-methylbenzyloxy 180 aminocarbonylmethylm-hydroxycarbonyl-m-methylbenzyloxy 181 Me(3-hydroxycarbonyl-5-methylphenoxy) methyl 182 3-picolyl(3-hydroxycarbonyl-5-methylphenoxy) methyl 183 aminocarbonylmethyl(3-hydroxycarbonyl-5-methylphenoxy) methyl 184 Me o-phenylbenzyloxy 1853-picolyl o-phenylbenzyloxy 186 aminocarbonylmethyl o-phenylbenzyloxy187 Me m-phenylbenzyloxy 188 3-picolyl m-phenylbenzyloxy 189aminocarbonylmethyl m-phenylbenzyloxy 190 Me (naphth-1-yl)methoxy 1913-picolyl (naphth-1-yl)methoxy 192 aminocarbonylmethyl(naphth-1-yl)methoxy 193 Me (naphth-2-yl)methoxy 194 3-picolyl(naphth-2-yl)methoxy 195 aminocarbonylmethyl (naphth-2-yl)methoxy 196 Me(2-methylnaphth-1-yl)methoxy 197 3-picolyl (2-methylnaphth-1-yl)methoxy198 aminocarbonylmethyl (2-methylnaphth-1-yl)methoxy 199 Me(4-methylnaphth-2-yl)methoxy 200 3-picolyl (4-methylnaphth-2-yl)methoxy201 aminocarbonylmethyl (4-methylnaphth-2-yl)methoxy 202 Me(pyridin-3-yl)methoxy 203 3-picolyl (pyridin-3-yl)methoxy 204aminocarbonylmethyl (pyridin-3-yl)methoxy 205 Me (pyridin-4-yl)methoxy206 3-picolyl (pyridin-4-yl)methoxy 207 aminocarbonylmethyl(pyridin-4-yl)methoxy 208 Me (3,5-dichloropyridin-4-yl)methoxy 2093-picolyl (3,5-dichloropyridin-4-yl)methoxy 210 aminocarbonylmethyl(3,5-dichloropyridin-4-yl)methoxy 211 Me(3,5-dimethylpyridin-4-yl)methoxy 212 3-picolyl(3,5-dimethylpyridin-4-yl)methoxy 213 aminocarbonylmethyl(3,5-dimethylpyridin-4-yl)methoxy 214 Me(1,2,3-benzotriazol-1-yl)methoxy 215 3-picolyl(1,2,3-benzotriazol-1-yl)methoxy 216 aminocarbonylmethyl(1,2,3-benzotriazol-1-yl)methoxy 217 Me benzhydroxy 218 3-picolylbenzhydroxy 219 aminocarbonylmethyl benzhydroxy 220 Mep-(1,2,3-thiadiazol-5-yl)benzyloxy 221 3-picolylp-(1,2,3-thiadiazol-5-yl)benzyloxy 222 aminocarbonylmethylp-(1,2,3-thiadiazol-5-yl)benzyloxy 223 Me o-(tetrazol-5-yl)benzyloxy 2243-picolyl o-(tetrazol-5-yl)benzyloxy 225 aminocarbonylmethylo-(tetrazol-5-yl)benzyloxy 226 Me m-(tetrazol-5-yl)benzyloxy 2273-picolyl m-(tetrazol-5-yl)benzyloxy 228 aminocarbonylmethylm-(tetrazol-5-yl)benzyloxy 229 Me[3-methyl-5-(tetrazol-5-yl)phenoxy]methyl 230 3-picolyl[3-methyl-5-(tetrazol-5-yl)phenoxy]methyl 231 aminocarbonylmethyl[3-methyl-5-(tetrazol-5-yl)phenoxy]methyl 232 Mem-methyl-m-(tetrazol-5-yl)benzyloxy 233 3-picolylm-methyl-m-(tetrazol-5-yl)benzyloxy 234 aminocarbonylmethylm-methyl-m-(tetrazol-5-yl)benzyloxy 235 Me 2-oxo-2-phenylethoxy 2363-picolyl 2-oxo-2-phenylethoxy 237 aminocarbonylmethyl2-oxo-2-phenylethoxy 238 Me carbo-t-butoxymethoxy 239 3-picolylcarbo-t-butoxymethoxy 240 aminocarbonylmethyl carbo-t-butoxymethoxy 241Me (benzimidazol-2-yl)methoxy 242 3-picolyl (benzimidazol-2-yl)methoxy243 aminocarbonylmethyl (benzimidazol-2-yl)methoxy 244 Me(imidazol-2-yl)methoxy 245 3-picolyl (imidazol-2-yl)methoxy 246aminocarbonylmethyl (imidazol-2-yl)methoxy 247 Me(1,4-dimethylimidazol-5-yl)methoxy 248 3-picolyl(1,4-dimethylimidazol-5-yl)methoxy 249 aminocarbonylmethyl(1,4-dimethylimidazol-5-yl)methoxy 250 Me (thiazol-4-yl)methoxy 2513-picolyl (thiazol-4-yl)methoxy 252 aminocarbonylmethyl(thiazol-4-yl)methoxy 253 Me (quinolin-2-yl)methoxy 254 3-picolyl(quinolin-2-yl)methoxy 255 aminocarbonylmethyl (quinolin-2-yl)methoxy256 Me (1,3-benzodioxo-5-yl)methoxy 257 3-picolyl(1,3-benzodioxo-5-yl)methoxy 258 aminocarbonylmethyl(1,3-benzodioxo-5-yl)methoxy 259 Me (3,5-dimethylisoxazol-4-yl)methoxy260 3-picolyl (3,5-dimethylisoxazol-4-yl)methoxy 261 aminocarbonylmethyl(3,5-dimethylisoxazol-4-yl)methoxy 262 Me(3,5-dimethylpyrazol-1-yl)methoxy 263 3-picolyl(3,5-dimethylpyrazol-1-yl)methoxy 264 aminocarbonylmethyl(3,5-dimethylpyrazol-1-yl)methoxy 265 Me(1,3,5-trimethylpyrazol-4-yl)methoxy 266 3-picolyl(1,3,5-trimethylpyrazol-4-yl)methoxy 267 aminocarbonylmethyl(1,3,5-trimethylpyrazol-4-yl)methoxy

TABLE 6

A1 (R⁴ = H) A2 (R⁴ = OH) A3 (R⁴ = NH₂)

B1 (R⁴ = H) B2 (R⁴ = OH) B3 (R⁴ = NH₂)

C1 (R⁴ = H) C2 (R⁴ = OH) C3 (R⁴ = NH₂)

D1 (R⁴ = H) D2 (R⁴ = OH) D3 (R⁴ = NH₂)

E1 (R⁴ = H) E2 (R⁴ = OH) E3 (R⁴ = NH₂)

F1 (R⁴ = H) F2 (R⁴ = OH) F3 (R⁴ = NH₂)

G1 (R⁴ = H) G2 (R⁴ = OH) G3 (R⁴ = NH₂)

H1 (R⁴ = H) H2 (R⁴ = OH) H3 (R⁴ = NH₂)

I1 (R⁴ = H) I2 (R⁴ = OH) I3 (R⁴ = NH₂)

J1 (R⁴ = H) J2 (R⁴ = OH) J3 (R⁴ = NH₂)

K1 (R⁴ = H) K2 (R⁴ = OH) K3 (R⁴ = NH₂)

L1 (R⁴ = H) L2 (R⁴ = OH) L3 (R⁴ = NH₂) Ex # R^(b’) R^(3’) 1 Me H 23-picolyl H 3 aminocarbonylmethyl H 4 Me methyl 5 3-picolyl methyl 6aminocarbonylmethyl methyl 7 Me ethyl 8 3-picolyl ethyl 9aminocarbonylmethyl ethyl 10 Me isopropyl 11 3-picolyl isopropyl 12aminocarbonylmethyl isopropyl 13 Me phenyl 14 3-picolyl phenyl 15aminocarbonylmethyl phenyl 16 Me benzyl 17 3-picolyl benzyl 18aminocarbonylmethyl benzyl 19 Me 2-phenylethyl 20 3-picolyl2-phenylethyl 21 aminocarbonylmethyl 2-phenylethyl 22 Me2-(2-methylphenyl)ethyl 23 3-picolyl 2-(2-methylphenyl)ethyl 24aminocarbonylmethyl 2-(2-methylphenyl)ethyl 25 Me2-(3-methylphenyl)ethyl 26 3-picolyl 2-(3-methylphenyl)ethyl 27aminocarbonylmethyl 2-(3-methylphenyl)ethyl 28 Me2-(2,6-dimethylphenyl)ethyl 29 3-picolyl 2-(2,6-dimethylphenyl)ethyl 30aminocarbonylmethyl 2-(2,6-dimethylphenyl)ethyl 31 Me2-(3,5-dimethylphenyl)ethyl 32 3-picolyl 2-(3,5-dimethylphenyl)ethyl 33aminocarbonylmethyl 2-(3,5-dimethylphenyl)ethyl 34 Me2-(3-amino-5-methylphenyl)ethyl 35 3-picolyl2-(3-amino-5-methylphenyl)ethyl 36 aminocarbonylmethyl2-(3-amino-5-methylphenyl)ethyl 37 Me 2-(pyridin-4-yl)ethyl 38 3-picolyl2-(pyridin-4-yl)ethyl 39 aminocarbonylmethyl 2-(pyridin-4-yl)ethyl 40 Me2-(2,6-dimethylpyridin-4-yl)ethyl 41 3-picolyl2-(2,6-dimethylpyridin-4-yl)ethyl 42 aminocarbonylmethyl2-(2,6-dimethylpyridin-4-yl)ethyl 43 Me2-(3,5-dimethylpyridin-4-yl)ethyl 44 3-picolyl2-(3,5-dimethylpyridin-4-yl)ethyl 45 aminocarbonylmethyl2-(3,5-dimethylpyridin-4-yl)ethyl 46 Me styryl 47 3-picolyl styryl 48aminocarbonylmethyl styryl 49 Me hydroxy 50 3-picolyl hydroxy 51aminocarbonylmethyl hydroxy 52 Me methoxy 53 3-picolyl methoxy 54aminocarbonylmethyl methoxy 55 Me ethoxy 56 3-picolyl ethoxy 57aminocarbonylmethyl ethoxy 58 Me isopropyloxy 59 3-picolyl isopropyloxy60 aminocarbonylmethyl isopropyloxy 61 Me tert-butoxy 62 3-picolyltert-butoxy 63 aminocarbonylmethyl tert-butoxy 64 Me cyclohexyloxy 653-picolyl cyclohexyloxy 66 aminocarbonylmethyl cyclohexyloxy 67 Mephenoxy 68 3-picolyl phenoxy 69 aminocarbonylmethyl phenoxy 70 Meo-methylphenoxy 71 3-picolyl o-methylphenoxy 72 aminocarbonylmethylo-methylphenoxy 73 Me m-methylphenoxy 74 3-picolyl m-methylphenoxy 75aminocarbonylmethyl m-methylphenoxy 76 Me cinnamyloxy 77 3-picolylcinnamyloxy 78 aminocarbonylmethyl cinnamyloxy 79 Me benzyloxy 803-picolyl benzyloxy 81 aminocarbonylmethyl benzyloxy 82 Me phenoxymethyl83 3-picolyl phenoxymethyl 84 aminocarbonylmethyl phenoxymethyl 85 Meo-methylbenzyloxy 86 3-picolyl o-methylbenzyloxy 87 aminocarbonylmethylo-methylbenzyloxy 88 Me m-methylbenzyloxy 89 3-picolyl m-methylbenzyloxy90 aminocarbonylmethyl m-methylbenzyloxy 91 Me o,o-dimethylbenzyloxy 923-picolyl o,o-dimethylbenzyloxy 93 aminocarbonylmethylo,o-dimethylbenzyloxy 94 Me (2,6-dimethylphenoxy)methyl 95 3-picolyl(2,6-dimethylphenoxy)methyl 96 aminocarbonylmethyl(2,6-dimethylphenoxy)methyl 97 Me m,m-dimethylbenzyloxy 98 3-picolylm,m-dimethylbenzyloxy 99 aminocarbonylmethyl m,m-dimethylbenzyloxy 100Me (3,5-dimethylphenoxy)methyl 101 3-picolyl (3,5-dimethylphenoxy)methyl102 aminocarbonylmethyl (3,5-dimethylphenoxy)methyl 103 Meo,o-dicyanobenzyloxy 104 3-picolyl o,o-dicyanobenzyloxy 105aminocarbonylmethyl o,o-dicyanobenzyloxy 106 Me m,m-dicyanobenzyloxy 1073-picolyl m,m-dicyanobenzyloxy 108 aminocarbonylmethylm,m-dicyanobenzyloxy 109 Me (2,6-dicyanophenoxy)methyl 110 3-picolyl(2,6-dicyanophenoxy)methyl 111 aminocarbonylmethyl(2,6-dicyanophenoxy)methyl 112 Me (3,5-dicyanophenoxy)methyl 1133-picolyl (3,5-dicyanophenoxy)methyl 114 aminocarbonylmethyl(3,5-dicyanophenoxy)methyl 115 Me o-amino-o-cyanobenzyloxy 116 3-picolylo-amino-o-cyanobenzyloxy 117 aminocarbonylmethylo-amino-o-cyanobenzyloxy 118 Me m-amino-m-cyanobenzyloxy 119 3-picolylm-amino-m-cyanobenzyloxy 120 aminocarbonylmethylm-amino-m-cyanobenzyloxy 121 Me o-amino-o-nitrobenzyloxy 122 3-picolylo-amino-o-nitrobenzyloxy 123 aminocarbonylmethylo-amino-o-nitrobenzyloxy 124 Me m-amino-m-nitrobenzyloxy 125 3-picolylm-amino-m-nitrobenzyloxy 126 aminocarbonylmethylm-amino-m-nitrobenzyloxy 127 Me p-amino-m,m-dimethylbenzyloxy 1283-picolyl p-amino-m,m-dimethylbenzyloxy 129 aminocarbonylmethylp-amino-m,m-dimethylbenzyloxy 130 Me o-amino-o-methylbenzyloxy 1313-picolyl o-amino-o-methylbenzyloxy 132 aminocarbonylmethylo-amino-o-methylbenzyloxy 133 Me m-amino-m-methylbenzyloxy 134 3-picolylm-amino-m-methylbenzyloxy 135 aminocarbonylmethylm-amino-m-methylbenzyloxy 136 Me o-cyano-o-methylbenzyloxy 137 3-picolylo-cyano-o-methylbenzyloxy 138 aminocarbonylmethylo-cyano-o-methylbenzyloxy 139 Me m-cyano-m-methylbenzyloxy 140 3-picolylm-cyano-m-methylbenzyloxy 141 aminocarbonylmethylm-cyano-m-methylbenzyloxy 142 Me o-cyano-o-nitrobenzyloxy 143 3-picolylo-cyano-o-nitrobenzyloxy 144 aminocarbonylmethylo-cyano-o-nitrobenzyloxy 145 Me (2-cyano-6-nitrophenoxy)methyl 1463-picolyl (2-cyano-6-nitrophenoxy)methyl 147 aminocarbonylmethyl(2-cyano-6-nitrophenoxy)methyl 148 Me m-cyano-m-nitrobenzyloxy 1493-picolyl m-cyano-m-nitrobenzyloxy 150 aminocarbonylmethylm-cyano-m-nitrobenzyloxy 151 Me (3-cyano-5-nitrophenoxy)methyl 1523-picolyl (3-cyano-5-nitrophenoxy)methyl 153 aminocarbonylmethyl(3-cyano-5-nitrophenoxy)methyl 154 Me m,m-dimethoxybenzyloxy 1553-picolyl m,m-dimethoxybenzyloxy 156 aminocarbonylmethylm,m-dimethoxybenzyloxy 157 Me m,m-dichlorobenzyloxy 158 3-picolylm,m-dichlorobenzyloxy 159 aminocarbonylmethyl m,m-dichlorobenzyloxy 160Me (3,5-dichlorophenoxy)methyl 161 3-picolyl (3,5-dichlorophenoxy)methyl162 aminocarbonylmethyl (3,5-dichlorophenoxy)methyl 163 Mem,m-dibromobenzyloxy 164 3-picolyl m,m-dibromobenzyloxy 165aminocarbonylmethyl m,m-dibromobenzyloxy 166 Mem,m-bis(trifluoromethyl)benzyloxy 167 3-picolylm,m-bis(trifluoromethyl)benzyloxy 168 aminocarbonylmethylm,m-bis(trifluoromethyl)benzyloxy 169 Me[3,5-bis(trifluoromethyl)phenoxy]methyl 170 3-picolyl[3,5-bis(trifluoromethyl)phenoxy]methyl 171 aminocarbonylmethyl[3,5-bis(trifluoromethyl)phenoxy]methyl 172 Mem-carboxamido-m-methylbenzyloxy 173 3-picolylm-carboxamido-m-methylbenzyloxy 174 aminocarbonylmethylm-carboxamido-m-methylbenzyloxy 175 Me(3-carboxamido-5-methylphenoxy)methyl 176 3-picolyl(3-carboxamido-5-methylphenoxy)methyl 177 aminocarbonylmethyl(3-carboxamido-5-methylphenoxy)methyl 178 Mem-hydroxycarbonyl-m-methylbenzyloxy 179 3-picolylm-hydroxycarbonyl-m-methylbenzyloxy 180 aminocarbonylmethylm-hydroxycarbonyl-m-methylbenzyloxy 181 Me(3-hydroxycarbonyl-5-methylphenoxy)methyl 182 3-picolyl(3-hydroxycarbonyl-5-methylphenoxy)methyl 183 aminocarbonylmethyl(3-hydroxycarbonyl-5-methylphenoxy)methyl 184 Me o-phenylbenzyloxy 1853-picolyl o-phenylbenzyloxy 186 aminocarbonylmethyl o-phenylbenzyloxy187 Me m-phenylbenzyloxy 188 3-picolyl m-phenylbenzyloxy 189aminocarbonylmethyl m-phenylbenzyloxy 190 Me (naphth-1-yl)methoxy 1913-picolyl (naphth-1-yl)methoxy 192 aminocarbonylmethyl(naphth-1-yl)methoxy 193 Me (naphth-2-yl)methoxy 194 3-picolyl(naphth-2-yl)methoxy 195 aminocarbonylmethyl (naphth-2-yl)methoxy 196 Me(2-methylnaphth-1-yl)methoxy 197 3-picolyl (2-methylnaphth-1-yl)methoxy198 aminocarbonylmethyl (2-methylnaphth-1-yl)methoxy 199 Me(4-methylnaphth-2-yl)methoxy 200 3-picolyl (4-methylnaphth-2-yl)methoxy201 aminocarbonylmethyl (4-methylnaphth-2-yl)methoxy 202 Me(pyridin-3-yl)methoxy 203 3-picolyl (pyridin-3-yl)methoxy 204aminocarbonylmethyl (pyridin-3-yl)methoxy 205 Me (pyridin-4-yl)methoxy206 3-picolyl (pyridin-4-yl)methoxy 207 aminocarbonylmethyl(pyridin-4-yl)methoxy 208 Me (3,5-dichloropyridin-4-yl)methoxy 2093-picolyl (3,5-dichloropyridin-4-yl)methoxy 210 aminocarbonylmethyl(3,5-dichloropyridin-4-yl)methoxy 211 Me(3,5-dimethylpyridin-4-yl)methoxy 212 3-picolyl(3,5-dimethylpyridin-4-yl)methoxy 213 aminocarbonylmethyl(3,5-dimethylpyridin-4-yl)methoxy 214 Me(1,2,3-benzotriazol-1-yl)methoxy 215 3-picolyl(1,2,3-benzotriazol-1-yl)methoxy 216 aminocarbonylmethyl(1,2,3-benzotriazol-1-yl)methoxy 217 Me benzhydroxy 218 3-picolylbenzhydroxy 219 aminocarbonylmethyl benzhydroxy 220 Mep-(1,2,3-thiadiazol-5-yl)benzyloxy 221 3-picolylp-(1,2,3-thiadiazol-5-yl)benzyloxy 222 aminocarbonylmethylp-(1,2,3-thiadiazol-5-yl)benzyloxy 223 Me o-(tetrazol-5-yl)benzyloxy 2243-picolyl o-(tetrazol-5-yl)benzyloxy 225 aminocarbonylmethylo-(tetrazol-5-yl)benzyloxy 226 Me m-(tetrazol-5-yl)benzyloxy 2273-picolyl m-(tetrazol-5-yl)benzyloxy 228 aminocarbonylmethylm-(tetrazol-5-yl)benzyloxy 229 Me[3-methyl-5-(tetrazol-5-yl)phenoxy]methyl 230 3-picolyl[3-methyl-5-(tetrazol-5-yl)phenoxy]methyl 231 aminocarbonylmethyl[3-methyl-5-(tetrazol-5-yl)phenoxy]methyl 232 Mem-methyl-m-(tetrazol-5-yl)benzyloxy 233 3-picolylm-methyl-m-(tetrazol-5-yl)benzyloxy 234 aminocarbonylmethylm-methyl-m-(tetrazol-5-yl)benzyloxy 235 Me 2-oxo-2-phenylethoxy 2363-picolyl 2-oxo-2-phenylethoxy 237 aminocarbonylmethyl2-oxo-2-phenylethoxy 238 Me carbo-t-butoxymethoxy 239 3-picolylcarbo-t-butoxymethoxy 240 aminocarbonylmethyl carbo-t-butoxymethoxy 241Me (benzimidazol-2-yl)methoxy 242 3-picolyl (benzimidazol-2-yl)methoxy243 aminocarbonylmethyl (benzimidazol-2-yl)methoxy 244 Me(imidazol-2-yl)methoxy 245 3-picolyl (imidazol-2-yl)methoxy 246aminocarbonylmethyl (imidazol-2-yl)methoxy 247 Me(1,4-dimethylimidazol-5-yl)methoxy 248 3-picolyl(1,4-dimethylimidazol-5-yl)methoxy 249 aminocarbonylmethyl(1,4-dimethylimidazol-5-yl)methoxy 250 Me (thiazol-4-yl)methoxy 2513-picolyl (thiazol-4-yl)methoxy 252 aminocarbonylmethyl(thiazol-4-yl)methoxy 253 Me (quinolin-2-yl)methoxy 254 3-picolyl(quinolin-2-yl)methoxy 255 aminocarbonylmethyl (quinolin-2-yl)methoxy256 Me (1,3-benzodioxo-5-yl)methoxy 257 3-picolyl(1,3-benzodioxo-5-yl)methoxy 258 aminocarbonylmethyl(1,3-benzodioxo-5-yl)methoxy 259 Me (3,5-dimethylisoxazol-4-yl)methoxy260 3-picolyl (3,5-dimethylisoxazol-4-yl)methoxy 261 aminocarbonylmethyl(3,5-dimethylisoxazol-4-yl)methoxy 262 Me(3,5-dimethylpyrazol-1-yl)methoxy 263 3-picolyl(3,5-dimethylpyrazol-1-yl)methoxy 264 aminocarbonylmethyl(3,5-dimethylpyrazol-1-yl)methoxy 265 Me(1,3,5-trimethylpyrazol-4-yl)methoxy 266 3-picolyl(1,3,5-trimethylpyrazol-4-yl)methoxy 267 aminocarbonylmethyl(1,3,5-trimethylpyrazol-4-yl)methoxy 268 Me 4-quinolinylmethoxy 2693-picolyl 4-quinolinylmethoxy 270 aminocarbonylmethyl4-quinolinylmethoxy 271 Me 2-methyl-4-quinolinylmethoxy 272 3-picolyl2-methyl-4-quinolinylmethoxy 273 aminocarbonylmethyl2-methyl-4-quinolinylmethoxy 274 Me 4-quinolinyloxymethyl 275 3-picolyl4-quinolinyloxymethyl 276 aminocarbonylmethyl 4-quinolinyloxymethyl

Utility

The compounds of formula I are expected to possess matrixmetalloproteinase and/or aggrecanase and/or TNF inhibitory activity. TheMMP inhibitory activity of the compounds of the present invention isdemonstrated using assays of MMP activity, for example, using the assaydescribed below for assaying inhibitors of MMP activity. The compoundsof the present invention are expected to be bioavailable in vivo asdemonstrated, for example, using the ex vivo assay described below. Thecompounds of formula I are expected to have the ability tosuppress/inhibit cartilage degradation in vivo, for example, asdemonstrated using the animal model of acute cartilage degradationdescribed below.

The compounds provided by this invention should also be useful asstandards and reagents in determining the ability of a potentialpharmaceutical to inhibit MPs. These would be provided in commercialkits comprising a compound of this invention.

Metalloproteinases have also been implicated in the degradation ofbasement membranes to allow infiltration of cancer cells into thecirculation and subsequent penetration into other tissues leading totumor metastasis (Stetler-Stevenson, Cancer and Metastasis Reviews,1990, 9, 289-303). The compounds of the present invention should beuseful for the prevention and treatment of invasive tumors by inhibitionof this aspect of metastasis.

The compounds of the present invention should also have utility for theprevention and treatment of osteopenia associated with matrixmetalloproteinase-mediated breakdown of cartilage and bone which occursin osteoporosis patients.

Compounds which inhibit the production or action of TNF and/orAggrecanase and/or MP's are potentially useful for the treatment orprophylaxis of various inflammatory, infectious, immunological ormalignant diseases. These include, but are not limited to inflammation,fever, cardiovascular effects, hemorrhage, coagulation and acute phaseresponse, an acute infection, septic shock, haemodynamic shock andsepsis syndrome, post ischaemic reperfusion injury, malaria, Crohn'sdisease, mycobacterial infection, meningitis, psoriasis, periodontits,gingivitis, congestive heart failure, fibrotic disease, cachexia, andaneroxia, graft rejection, cancer, corneal ulceration or tumor invasionby secondary metastases, autoimmune disease, skin inflammatory diseases,multiple osteo and rheumatoid arthritis, multiple sclerosis, radiationdamage, HIV, and hyperoxic alveolar injury.

Some compounds of the present invention have been shown to inhibit TNFproduction in lipopolysacharride stimulated mice, for example, using theassay for TNF induction in mice and in human whole blood as describedbelow.

Some compounds of the present invention have been shown to inhibitaggrecanase, a key enzyme in cartilage breakdown, as determined by theaggrecanase assay described below.

As used herein “μg” denotes microgram, “mg” denotes milligram, “g”denotes gram, “μL” denotes microliter “mL” denotes milliliter “L”denotes liter “nM” denotes nanomolar “μM” denotes micromolar “mM”denotes millimolar “M” denotes molar and “nm” denotes nanometer. “Sigma”stands for the Sigma-Aldrich Corp. of St. Louis, Mo.

A compound is considered to be active if it has an IC₅₀ or K_(i) valueof less than about 1 mM for the inhibition of MP.

Aggrecanase Enzymatic Assay

A novel enzymatic assay was developed to detect potential inhibitors ofaggrecanase. The assay uses active aggrecanase accumulated in media fromstimulated bovine nasal cartilage (BNC) or related cartilage sources andpurified cartilage aggrecan monomer or a fragment thereof as asubstrate.

The substrate concentration, amount of aggrecanase, time of incubationand amount of product loaded for Western analysis were optimized for useof this assay in screening putative aggrecanase inhibitors. Aggrecanaseis generated by stimulation of cartilage slices with interleukin-1(IL-1), tumor necrosis factor alpha (TNFα) or other stimuli. Matrixmetalloproteinases (MMPs) are secreted from cartilage in an inactive,zymogen form following stimulation, although active enzymes are presentwithin the matrix. We have shown that following depletion of theextracellular aggrecan matrix, active MMPs are released into the culturemedia (Tortorella et. al. Trans. Ortho. Res. Soc. 1995, 20, 341).Therefore, in order to accumulate BNC aggrecanase in culture media,cartilage is first depleted of endogenous aggrecan by stimulation with500 ng/mL human recombinant IL-β3 for 6 days with media changes every 2days. Cartilage is then stimulated for an additional 8 days withoutmedia change to allow accumulation of soluble, active aggrecanase in theculture media. In order to decrease the amount of other matrixmetalloproteinases released into the media during aggrecanaseaccumulation, agents which inhibit MMP-1, -2, -3, and -9 biosynthesisare included during stimulation. This BNC conditioned media, containingaggrecanase activity is then used as the source of aggrecanase for theassay. Aggrecanase enzymatic activity is detected by monitoringproduction of aggrecan fragments produced exclusively by cleavage at theGlu373-Ala374 bond within the aggrecan core protein by Western analysisusing the monoclonal antibody, BC-3 (Hughes et al., Biochem J. 1995,306, 799-804). This antibody recognizes aggrecan fragments with theN-terminus, 374ARGSVIL, generated upon cleavage by aggrecanase. The BC-3antibody recognizes this neoepitope only when it is at the N-terminusand not when it is present internally within aggrecan fragments orwithin the aggrecan protein core. Other proteases produced by cartilagein response to IL-1 do not cleave aggrecan at the Glu373-Ala374aggrecanase site; therefore, only products produced upon cleavage byaggrecanase are detected. Kinetic studies using this assay yield a Km of1.5+/−0.35 uM for aggrecanase.

To evaluate inhibition of aggrecanase, compounds are prepared as 10 mMstocks in DMSO, water or other solvents and diluted to appropriateconcentrations in water. Drug (50 μL) is added to 50 μL ofaggrecanase-containing media and 50 ul of 2 mg/mL aggrecan substrate andbrought to a final volume of 200 μL in 0.2 M Tris, pH 7.6, containing0.4 M NaCl and 40 mM CaCl₂. The assay is run for 4 hr at 37° C.,quenched with 20 mM EDTA and analyzed for aggrecanase-generatedproducts. A sample containing enzyme and substrate without drug isincluded as a positive control and enzyme incubated in the absence ofsubstrate serves as a measure of background.

Removal of the glycosaminoglycan side chains from aggrecan is necessaryfor the BC-3 antibody to recognize the ARGSVIL epitope on the coreprotein. Therefore, for analysis of aggrecan fragments generated bycleavage at the Glu373-Ala374 site, proteoglycans and proteoglycanfragments are enzymatically deglycosylated with chondroitinase ABC (0.1units/10 μg GAG) for 2 hr at 37° C. and then with keratanase (0.1units/10 μg GAG) and keratanase II (0.002 units/10 μg GAG) for 2 hr at37° C. in buffer containing 50 mM sodium acetate, 0.1 M Tris/HCl, pH6.5. After digestion, aggrecan in the samples is precipitated with 5volumes of acetone and resuspended in 30 μL of Tris glycine SDS samplebuffer (Novex) containing 2.5% beta mercaptoethanol. Samples are loadedand then separated by SDS-PAGE under reducing conditions with 4-12%gradient gels, transferred to nitrocellulose and immunolocated with1:500 dilution of antibody BC3. Subsequently, membranes are incubatedwith a 1:5000 dilution of goat anti-mouse IgG alkaline phosphatasesecond antibody and aggrecan catabolites visualized by incubation withappropriate substrate for 10-30 minutes to achieve optimal colordevelopment. Blots are quantitated by scanning densitometry andinhibition of aggrecanase determined by comparing the amount of productproduced in the presence versus absence of compound.

MMP Screens

The enzymatic activities of recombinant MMP-1, 2, 3, 9, and 13 weremeasured at 25° C. with a fluorometric assay (Copeland, R. A.; Lombardo,D.; Giannaras, J. and Decicco, C. P. Bioorganic Med. Chem. Lett. 1995,5, 1947-1952). Final enzyme concentrations in the assay were between0.05 and 10 nM depending on the enzyme and the potency of the inhibitortested. The permisive peptide substrate,MCA-Pro-Leu-Gly-Leu-DPA-Ala-Arg-NH₂, was present at a finalconcentration of 10 uM in all assays. Initial velocities, in thepresence or absence of inhibitor, were measured as slopes of the linearportion of the product progress curves. IC50 values were determined byplotting the inhibitor concentration dependence of the fractionalvelocity for each enzyme, and fitting the data by non-linear leastsquares methods to the standard isotherm equation (Copeland, R. A.Enzymes: A practical Introduction to Structure, Mechanism and DataAnalysis, Wiley-VHC, New York, 1996, 187-223). All of the amides studiedhere were assumed to act as competitive inhibitors of the enzyme,binding to the active site Zn atom as previously demonstrated bycrystallographic studies of MMP-3 complexed with related hydroxamicacids (Rockwell, A.; Melden, M.; Copeland, R. A.; Hardman, K.; Decicco,C. P. and DeGrado, W. F. J. Am. Chem. Soc. 1996, 118, 10337-10338).Based on the assumption of competitive inhibiton, the IC50 values wereconverted to Ki values.

PBMC ASSAY

Human peripheral blood mononuclear cells (PBMC) were obtained fromnormal donor blood by leukophoresis and isolated by Ficoll-Paque densityseparation. PBMCs were suspended in 0.5 ml RPMI 1640 with no serum at2×10⁶ cells/ml in 96 well polystyrene plates. Cells were preincubated 10minutes with compound, then stimulated with 1 μg/ml LPS(Lipopolysaccharide, Salmonella typhimurium) to induce TNF production.After an incubation of 5 hours at 37° C. in 95% air, 5% CO₂ environment,culture supernatants were removed and tested by standard sandwich ELISAfor TNF production.

TNF Human Whole Blood Assay

Blood is drawn from normal donors into tubes containing 143 USP units ofheparin/10 mL. 225 μL of blood is plated directly into sterilepolypropylene tubes. Compounds are diluted in DMSO/serum free media andadded to the blood samples so the final concentration of compounds are50, 10, 5, 1, 0.5, 0.1, and 0.01 μM. The final concentration of DMSOdoes not exceed 0.5%. Compounds are preincubated for 15 minutes beforethe addition of 100 ng/mL LPS. Plates are incubated for 5 hours in anatmosphere of 5% CO₂ in air. At the end of 5 hours, 750 μL of serum freemedia is added to each tube and the samples are spun at 1200 RPM for 10minutes. The supernatant is collected off the top and assayed forTNF-alpha production by a standard sandwich ELISA. The ability ofcompounds to inhibit TNF-alpha production by 50% compared to DMSOtreated cultures is given by the IC50 value.

TNF Induction in Mice

Test compounds are administered to mice either I.P. or P.O. at timezero. Immediately following compound administration, mice receive anI.P. injection of 20 mg of D-galactosamine plus 10 μg oflipopolysaccharide. One hour later, animals are anesthetized and bled bycardiac puncture. Blood plasma is evaluated for TNF levels by an ELISAspecific for mouse TNF. Administration of representative compounds ofthe present invention to mice results in a dose-dependent suppression ofplasma TNF levels at one hour in the above assay.

Dosage and Formulation

The compounds of the present invention can be administered orally usingany pharmaceutically acceptable dosage form known in the art for suchadministration. The active ingredient can be supplied in solid dosageforms such as dry powders, granules, tablets or capsules, or in liquiddosage forms, such as syrups or aqueous suspensions. The activeingredient can be administered alone, but is generally administered witha pharmaceutical carrier. A valuable treatise with respect topharmaceutical dosage forms is Remington's Pharmaceutical Sciences, MackPublishing.

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, theymay also be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form, all using dosageforms well known to those of ordinary skill in the pharmaceutical arts.An effective but non-toxic amount of the compound desired can beemployed as an antiinflammatory and antiarthritic agent.

The compounds of this invention can be administered by any means thatproduces contact of the active agent with the agent's site of action inthe body of a mammal. They can be administered by any conventional meansavailable for use in conjunction with pharmaceuticals, either asindividual therapeutic agents or in a combination of therapeutic agents.They can be administered alone, but generally administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient,and theeffect desired. An ordinarily skilled physician or veterinarian canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter, or arrest the progress of the condition.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. For a normal male adult human of approximately 70kg of body weight, this translates into a dosage of 70 to 1400 mg/day.Intravenously, the most preferred doses will range from about 1 to about10 mg/kg/minute during a constant rate infusion. Advantageously,compounds of the present invention may be administered in a single dailydose, or the total daily dosage may be administered in divided doses oftwo, three, or four times daily.

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wallknown to those of ordinary skill in that art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittant throughout the dosageregimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients, orcarriers (collectively referred to herein as carrier materials) suitablyselected with respect to the intended form of administration, that is,oral tablets, capsules, elixirs, syrups and the like, and consistentwith conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamallar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition. Theactive ingredient can be administered orally in solid dosage forms, suchas capsules, tablets, and powders, or in liquid dosage forms, such aselixirs, syrups, and suspensions. It can also be administeredparenterally, in sterile liquid dosage forms.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field. Useful pharmaceutical dosage-forms foradministration of the compounds of this invention can be illustrated asfollows:

Capsules

Capsules are prepared by conventional procedures so that the dosage unitis 500 milligrams of active ingredient, 100 milligrams of cellulose and10 milligrams of magnesium stearate.

A large number of unit capsules may also prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Syrup Wt. % Active Ingredient 10 Liquid Sugar 50 Sorbitol 20 Glycerine 5 Flavor, Colorant and as required Preservative Water as required

The final volume is brought up to 100% by the addition of distilledwater.

Aqueous Suspension Wt. % Active Ingredient 10 Sodium Saccharin 0.01Keltrol ® (Food Grade Xanthan Gum) 0.2 Liquid Sugar 5 Flavor, Colorantand as required Preservative Water as required

Xanthan gum is slowly added into distilled water before adding theactive ingredient and the rest of the formulation ingredients. The finalsuspension is passed through a homogenizer to assure the elegance of thefinal products.

Resuspendable Powder Wt. % Active Ingredient 50.0 Lactose 35.0 Sugar10.0 Acacia 4.7 Sodium Carboxylmethylcellulose 0.3

Each ingredient is finely pulverized and then uniformly mixed together.Alternatively, the powder can be prepared as a suspension and then spraydried.

Semi-Solid Gel Wt. % Active Ingredient 10 Sodium Saccharin 0.02 Gelatin2 Flavor, Colorant and as required Preservative Water as required

Gelatin is prepared in hot water. The finely pulverized activeingredient is suspended in the gelatin solution and then the rest of theingredients are mixed in. The suspension is filled into a suitablepackaging container and cooled down to form the gel.

Semi-Solid Paste Wt. % Active Ingredient 10 Gelcarin ® (Carrageenin gum)1 Sodium Saccharin 0.01 Gelatin 2 Flavor, Colorant and as requiredPreservative Water as required

Gelcarin® is dissolved in hot water (around 80° C.) and then thefine-powder active ingredient is suspended in this solution. Sodiumsaccharin and the rest of the formulation ingredients are added to thesuspension while it is still warm. The suspension is homogenized andthen filled into suitable containers.

Emulsifiable Paste Wt. % Active Ingredient 30 Tween ® 80 and Span ® 80 6Keltrol ® 0.5 Mineral Oil 63.5

All the ingredients are carefully mixed together to make a homogenouspaste.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil is prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules arewashed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 500 milligrams of active ingredient, 150 milligrams of lactose,50 milligrams of cellulose and 10 milligrams of magnesium stearate.

A large number of tablets may also be prepared by conventionalprocedures so that the dosage unit was 100 milligrams of activeingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams ofmagnesium stearate, 275 milligrams of microcrystalline cellulose, 11milligrams of starch and 98.8 milligrams of lactose. Appropriatecoatings may be applied to increase palatability or delay absorption.

Injectable A parenteral composition suitable for administration byinjection is prepared by stirring 1.5% by weight of active ingredient in10% by volume propylene glycol and water. The solution is made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension is prepared for oral administration so that each 5mL contain 100 mg of finely divided active ingredient, 200 mg of sodiumcarboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitolsolution, U.S.P., and 0.025 mL of vanillin.

The compounds of the present invention may be administered incombination with a second therapeutic agent, especially non-steroidalanti-inflammatory drugs (NSAID's). The compound of Formula I and suchsecond therapeutic agent can be administered separately or as a physicalcombination in a single dosage unit, in any dosage form and by variousroutes of administration, as described above.

The compound of Formula I may be formulated together with the secondtherapeutic agent in a single dosage unit (that is, combined together inone capsule, tablet, powder or liquid, etc.). When the compound ofFormula I and the second therapeutic agent are not formulated togetherin a single dosage unit, the compound of Formula I and the secondtherapeutic agent may be administered essentially at the same time, orin any order; for example the compound of Formula I may be administeredfirst, followed by administration of the second agent. When notadministered at the same time, preferably the administration of thecompound of Formula I and the second therapeutic agent occurs less thanabout one hour apart, more preferably less than about 5 to 30 minutesapart.

Preferably the route of administration of the compound of Formula I isoral. Although it is preferable that the compound of Formula I and thesecond therapeutic agent are both administered by the same route (thatis, for example, both orally), if desired, they may each be administeredby different routes and in different dosage forms (that is, for example,one component of the combination product may be administered orally, andanother component may be administered intravenously).

The dosage of the compound of Formula I when administered alone or incombination with a second therapeutic agent may vary depending uponvarious factors such as the pharmacodynamic characteristics of theparticular agent and its mode and route of administration, the age,health and weight of the recipient, the nature and extent of thesymptoms, the kind of concurrent treatment, the frequency of treatment,and the effect desired, as described above.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of Formula I and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with asustained-release material which effects a sustained-release throughoutthe gastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner will be readily apparent to those skilledin the art, once armed with the present disclosure.

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of osteoarthritis or rheumatoidarthritis, which comprise one or more containers containing apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula I. Such kits may further include, if desired,one or more of various conventional pharmaceutical kit components, suchas, for example, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, mayalso be included in the kit.

In the present disclosure it should be understood that the specifiedmaterials and conditions are important in practicing the invention butthat unspecified materials and conditions are not excluded so long asthey do not prevent the benefits of the invention from being realized.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations. Various equivalents, changes and modifications may be madewithout departing from the spirit and scope of this invention, and it isunderstood that such equivalent embodiments are part of this invention.

What is claimed is:
 1. A compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt form thereof,wherein; A is selected from COR⁵, —CO₂H, —CO₂R⁶, —CONHOH, —CONHOR⁵,—CONHOR⁶, —NHR^(a), —N(OH)COR⁵, —SH, —CH₂SH, —SONHR^(a), SN₂H₂R^(a),—S(O) (═NH)R^(a), —S(═NH)₂R^(a), PO(OH)₂, and PO(OH)NHR^(a); R¹ andR^(b′) taken together with the CR²—N to which they are attached form a4-8 membered cyclic amine containing from 0-1 double bonds, 0-1S(O)_(p), 0-1 oxygen atoms, and 0-1 NR^(a), and substituted with 0-1groups selected from OH and ═O and is substituted with 0-3 R^(b); R, ateach occurrence, is independently selected from H, CH₃, CH₂CH₃,CH(CH₃)₂, CH═CH₂, CH═CHCH₃, and CH₂CH═CH₂; R′, at each occurrence, isindependently selected from H, CH₃, CH₂CH₃, and CH(CH₃)₂; alternatively,R and R′ together with the carbon to which they are attached form acyclopropyl, cyclobutyl or cyclopentyl group; R² is selected from H,C₁₋₁₀ alkylene-H, C₂₋₁₀ alkenylene-H, C₂₋₁₀ alkynylene-H,(CRR′)_(r′)O(CRR′)_(r)—H, (CRR′)_(r′)NR^(a)(CRR′)_(r)—H, (CRR′)_(r′)C(O)(CRR′)_(r)—H, (CRR′)_(r′)C(O)O(CRR′)_(r)—H,(CRR′)_(r′)OC(O)(CRR′)_(r)—H, (CRR′)_(r′)C(O)NR^(a)(CRR′)_(r)—H,(CRR′)_(r′)NR^(a)C(O)(CRR′)_(r)—H, (CRR′)_(r′)OC(O)O(CRR′)_(r)—H,(CRR′)_(r′)OC(O)NR^(a)(CRR′)_(r)—H, (CRR′)_(r′)NR^(a)C(O)O(CRR′)_(r)—H,(CRR′)_(r′)NR^(a)C(O)NR^(a)(CRR′)_(r)—H,(CRR′)_(r′)S(O)_(p)(CRR′)_(r)—H, (CRR′)_(r′)SO₂NR^(a)(CRR′)_(r)—H,(CRR′)_(r′)NR^(a)SO₂(CRR′)_(r)—H, and(CRR′)_(r′)NR^(a)SO₂NR^(a)(CRR′)_(r)—H; R³ isU—X—Y—Z—U^(a)—X^(a)—Y^(a)—X¹—Z^(a); U is absent or is selected from: O,NR^(a), C(O), C(O)O, OC(O), C(O)NR^(a), NR^(a)C(O), OC(O)O, OC(O)NR^(a),NR^(a)C(O)O, NR^(a)C(O)NR^(a), S(O)_(p), S(O)_(p)NR^(a), NR^(a)S(O)_(p),and NR^(a)SO₂NR^(a); X is absent or selected from C₁₋₁₀ alkylene, C₂₋₁₀alkenylene, and C₂₋₁₀ alkynylene; Y is absent or selected from O,NR^(a), S(O)_(p), S(O)_(p)NR^(a), C(O)NR^(a), and C(O), provided thatwhen U and Y are present, X is present; Z is absent or selected from aC₃₋₁₃ carbocyclic residue substituted with 0-5 R^(d) and a 6 or 10membered heterocyclic system containing 1 N and substituted with 0-5R^(d); U^(a) is absent or is selected from: O, NR^(a), C(O), C(O)O,OC(O), C(O)NR^(a), NR^(a)C(O), OC(O)O, OC(O)NR^(a), NR^(a)C(O)O,NR^(a)C(O)NR^(a), S(O)_(p), S(O)_(p)NR^(a), NR^(a)S(O)_(p), andNR^(a)SO₂NR^(a); X^(a) is absent or selected from C₁₋₁₀ alkylene, C₂₋₁₀alkenylene, and C₂₋₁₀ alkynylene; Y^(a) is absent or selected from O,NR^(a), S(O)_(p), S(O)_(p)NR^(a), C(O)NR^(a), and C(O), provided thatwhen U^(a) and Y^(a) are present, X^(a) is present; X¹ is absent orselected from C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, and C₂₋₁₀ alkynylene;Z^(a) is quinoline substituted with 0-5 R^(d); R⁴ is selected from H,Q′, C₁₋₁₀ alkylene-Q′, C₂₋₁₀ alkenylene-Q′, C₂₋₁₀ alkynylene-Q′,(CRR′)_(r′)O(CRR′)_(r)—Q′, (CRR′)_(r′)NR^(a)(CRR′)_(r)—Q′,(CRR′)_(r′)NR^(a)C(O)(CRR′)_(r)—Q′, (CRR′)_(r′)C(O)NR^(a)(CRR′)_(r)—Q′,(CRR′)_(r′)C(O)(CRR′)_(r)—Q′, (CRR′)_(r′)C(O)O(CRR′)_(r)—Q′,(CRR′)_(r′)S(O)_(p)(CRR′)_(r)—Q′, (CRR′)_(r′)SO₂NR^(a)(CRR′)_(r)—Q′,(CRR′)_(r′)NR^(a)C(O)NR^(a)(CRR′)_(r)—Q′,(CRR′)_(r′)OC(O)NR^(a)(CRR′)_(r)—Q′, and(CRR′)_(r′)NR^(a)C(O)O(CRR′)_(r)—Q′; R^(4a) is selected from H, C₁₋₆alkyl, —C₁₋₆ alkyl-phenyl, and phenyl; Q′ is selected from H, a C₃₋₁₃carbocyclic residue substituted with 0-5 R^(b) and a 6 or 10 memberedheterocyclic system containing 1 N and substituted with 0-5 R^(b);R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,phenyl or benzyl; R^(a′), at each occurrence, is independently selectedfrom H, C₁₋₄ alkyl, phenyl or benzyl; R^(a″), at each occurrence, isindependently selected from C₁₋₄ alkyl, phenyl or benzyl; alternatively,R^(a) and R^(a′) taken together with the nitrogen to which they areattached form a 6 membered ring; R^(b) is selected from H, C₁₋₆ alkyl,phenyl, benzyl, C(O)R^(a), C(O)NR^(a)R^(a′), S(O)₂NR^(a)R^(a′), andS(O)_(p)R^(a″); R^(c), at each occurrence, is independently selectedfrom C₁₋₆ alkyl, OR^(a), Cl, F, Br, I, ═O, CN, NO₂, NR^(a)R^(a′),C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a′), NR^(a)C(O)NR^(a)R^(a′),OC(O)NR^(a)R^(a′), R^(a)NC(O)O, S(O)₂NR^(a)R^(a′), NR^(a)S(O)₂R^(a″),NR^(a)S(O)₂NR^(a)R^(a′), OS(O)₂NR^(a)R^(a′), NR^(a)S(O)₂O,S(O)_(p)R^(a″), CF₃, CF₂CF₃, —CH(═NOH), —C(═NOH)CH₃,(CRR′)_(s)O(CRR′)_(s′)R^(c′), (CRR′)_(s)S(O)_(p)(CRR′)_(s′)R^(c′),(CRR′)_(s)NR^(a)(CRR′)_(s′)R^(c′), C₃₋₁₀ carbocyclic residue and a 6 or10 membered heterocyclic system containing 1 N; R^(c′), at eachoccurrence, is independently selected from phenyl substituted with 0-3R^(b), biphenyl substituted with 0-2 R^(b), naphthyl substituted with0-3 R^(b) and a 6 or 10 membered heterocyclic system containing 1 N andsubstituted with 0-3 R^(b); R^(d), at each occurrence, is independentlyselected from C₁₋₆ alkyl, OR^(a), Cl, F, Br, I, ═O, CN, NO₂,NR^(a)R^(a′), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a′),NR^(a)C(O)NR^(a)R^(a′), OC(O)NR^(a)R^(a′), NR^(a)C(O)O,S(O)₂NR^(a)R^(a′), NR^(a)S(O)₂R^(a″), NR^(a)S(O)₂NR^(a)R^(a′),OS(O)₂NR^(a)R^(a′), NR^(a)S(O)₂O, S(O)_(p)R^(a″), CF₃, CF₂CF₃, C₃₋₁₀carbocyclic residue and a 6 or 10 membered heterocyclic systemcontaining 1 N; R⁵, at each occurrence, is selected from H, C₁₋₁₀ alkylsubstituted with 0-2 R^(e), and C₁₋₈ alkyl substituted with 0-2 R^(f);R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl,OR^(a), Cl, F, Br, I, ═O, CN, NO₂, NR^(a)R^(a′), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a′), S(O)₂NR^(a)R^(a′), S(O)_(p)R^(a″), CF₃, and CF₂CF₃;R^(f), at each occurrence, is selected from phenyl substituted with 0-2R^(e) and biphenyl substituted with 0-2 R^(e); R⁶, at each occurrence,is selected from phenyl, naphthyl, C₁₋₁₀ alkyl-phenyl-C₁₋₆ alkyl-, C₃₋₁₁cycloalkyl, C₁₋₆ alkylcarbonyloxy-C₁₋₃ alkyl-, C₁₋₆alkoxycarbonyloxy-C₁₋₃ alkyl-, C₂₋₁₀ alkoxycarbonyl, C₃₋₆cycloalkylcarbonyloxy-C₁₋₃ alkyl-, C₃₋₆ cycloalkoxycarbonyloxy-C₁₋₃alkyl-, C₃₋₆ cycloalkoxycarbonyl, phenoxycarbonyl,phenyloxycarbonyloxy-C₁₋₃ alkyl-, phenylcarbonyloxy-C₁₋₃ alkyl-, C₁₋₆alkoxy-C₁₋₆ alkylcarbonyloxy-C₁₋₃ alkyl-, [5-(C₁-C₅alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, —C₁₋₁₀ alkyl-NR⁷R^(7a),—CH(R⁸)OC(═O)R⁹, —CH(R⁸) OC(═O)OR⁹, and

R⁷ is selected from H and C₁₋₁₀ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-; R^(7a) is selected fromH and C₁₋₁₀ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl-C₁₋₃ alkyl-, andphenyl-C₁₋₆ alkyl-; R⁸ is selected from H and C₁₋₄ linear alkyl; R⁹ isselected from H, C₁₋₈ alkyl substituted with 1-2 R^(g), C₃₋₈ cycloalkylsubstituted with 1-2 R^(g), and phenyl substituted with 0-2 R^(e);R^(g), at each occurrence, is selected from C₁₋₄ alkyl, C₃₋₈ cycloalkyl,C₁₋₅ alkoxy, phenyl substituted with 0-2 R^(e); p, at each occurrence,is selected from 0, 1, and 2; r, at each occurrence, is selected from 0,1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; r′, at each occurrence, is selectedfrom 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and, s, at each occurrence,is selected from 0, 1, 2, and
 3. 2. A compound according to claim 1,wherein; A is selected from COR⁵, —CO₂H, —CONHOH, —CONHOR⁵, —CONHOR⁶,—N(OH)COR⁵, —SH, and —CH₂SH; R² is selected from H, C₁₋₆ alkylene-H,C₂₋₆ alkenylene-H, C₂₋₆ alkynylene-H, (CH₂)_(r′)O(CH₂)_(r)—H,(CH₂)_(r′)NR^(a)(CH₂)_(r)—H, (CH₂)_(r′)C(O) (CH₂)_(r)—H,(CH₂)_(r′)C(O)NR^(a)(CH₂)_(r)—H, (CH₂)_(r′)NR^(a)C(O)(CH₂)_(r)—H,(CH₂)_(r′)SO₂NR^(a)(CH₂)_(r)—H, and (CH₂)_(r′)NR^(a)SO₂(CH₂)_(r)—H; U isabsent or is selected from: O, NR^(a), C(O), C(O)NR^(a), and NR^(a)C(O);X is absent or selected from C₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆alkynylene; Y is absent or selected from O, NR^(a), C(O)NR^(a), andC(O), provided that when U and Y are present, X is present; Z is absentor selected from a C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(d)and a 6 or 10 membered heterocyclic system containing 1 N andsubstituted with 0-5 R^(d); U^(a) is absent or is selected from: O,NR^(a), C(O), C(O)NR^(a), and NR^(a)C(O); X^(a) is absent or selectedfrom C₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene; Y^(a) isabsent or selected from O, NR^(a), C(O)NR^(a), and C(O), provided thatwhen U^(a) and Y^(a) are present, X^(a) is present; X¹ is absent orselected from C₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene; R⁴ isselected from H, Q′, C₁₋₅ alkylene-Q′, C₂₋₅ alkenylene-Q′, C₂₋₅alkynylene-Q′, (CRR′)_(r′)O(CRR′)_(r)—Q′,(CRR′)_(r′)NR^(a)(CRR′)_(r)—Q′, (CRR′)_(r′)NR^(a)C(O)(CRR′)_(r)—Q′,(CRR′)_(r′)C(O)NR^(a)(CRR′)_(r)—Q′,(CRR′)_(r′)NR^(a)C(O)NR^(a)(CRR′)_(r)—Q′, (CRR′)_(r′)C(O) (CRR′)_(r)—Q′,(CRR′)_(r′)C(O)O(CRR′)_(r)—Q′, (CRR′)_(r′)S(O)_(p)(CRR′)_(r)—Q′, and(CRR′)_(r′)SO₂NR^(a)(CRR′)_(r)—Q′; R^(4a) is selected from H, C₁₋₄alkyl, —C₁₋₄ alkyl-phenyl, and phenyl; Q′ is selected from H, phenylsubstituted with 0-3 R^(b) and a 6 membered heteroaryl system containingfrom 1 N substituted with 0-3 R^(b); R^(c), at each occurrence, isindependently selected from C₁₋₆ alkyl, OR^(a), Cl, F, Br, I, ═O, CN,NO₂, NR^(a)R^(a′), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a′),R^(a)NC(O)NR^(a)R^(a′), OC(O)NR^(a)R^(a′), R^(a)NC(O)O,S(O)₂NR^(a)R^(a′), NR^(a)S(O)₂R^(a″), NR^(a)S(O)₂NR^(a)R^(a′),OS(O)₂NR^(a)R^(a′), NR^(a)S(O)₂O, S(O)_(p)R^(a″), CF₃, CF₂CF₃, C₅₋₁₀carbocyclic residue and a 6 or 10 membered heterocyclic systemcontaining 1 N; R^(d), at each occurrence, is independently selectedfrom C₁₋₆ alkyl, OR^(a), Cl, F, Br, I, ═O, CN, NO₂, NR^(a)R^(a′),C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a′), R^(a)NC(O)NR^(a)R^(a′),OC(O)NR^(a)R^(a′), R^(a)NC(O)O, S(O)₂NR^(a)R^(a′), NR^(a)S(O)₂R^(a′),NR^(a)S(O)₂NR^(a)R^(a′), OS(O)₂NR^(a)R^(a′), NR^(a)S(O)₂O,S(O)_(p)R^(a″), CF₃, CF₂CF₃, C₃₋₁₀ carbocyclic residue and a 6 or 10membered heterocyclic system containing 1 N; r, at each occurrence, isselected from 0, 1, 2, 3, 4, and 5; and, r′, at each occurrence, isselected from 0, 1, 2, 3, 4, and
 5. 3. A compound according to claim 2,wherein; A is selected from —CO₂H, —CONHOH, —CONHOR⁵, and —N(OH)COR⁵; R²is selected from H, CH₃, and CH₂CH₃; U is absent; X is absent or is C₁₋₃alkylene; Y is absent; Z is absent or is selected from a C₆₋₁₀ arylgroup substituted with 0-3 R^(d) and a 6 or 10 membered heterocyclicsystem containing 1 N and substituted with 0-3 R^(d); U^(a) is absent;X^(a) is absent or selected from C₁₋₃ alkylene and C₂₋₃ alkenylene;Y^(a) is absent or selected from O and NR^(a); X¹ is absent or is C₁₋₃alkylene; R⁴ is selected from H, C₁₋₅ alkylene-Q′,(CH₂)_(r′)O(CH₂)_(r)—Q′, and (CH₂)_(r′)NR^(a)(CH₂)_(r)—Q′; R^(4a) isselected from H and C₁₋₄ alkyl; Q′ is H or phenyl substituted with 0-3R^(b); R^(b′) is selected from H, C₁₋₄ alkylene-Q, C₂₋₄ alkenylene-Q,(CRR′)_(r′)O(CRR′)_(r)—Q, (CRR′)_(r′)NR^(a)(CRR′)_(r)—Q,(CRR′)_(r)C(O)(CRR′)_(r)—Q, (CRR′)_(r)C(O)NR^(a)(CRR′)_(r)—Q,(CRR′)_(r′)NR^(a)C(O)(CRR′)_(r)—Q; r, at each occurrence, is selectedfrom 0, 1, 2, and 3; and, r′, at each occurrence, is selected from 0, 1,2, and
 3. 4. A compound according to claim 3, wherein; A is selectedfrom —CO₂H, —CONHOH, and —CONHOR⁵; R² is H; X is absent or is CH₂ orCH₂CH₂; Z is absent or is selected from phenyl substituted with 0-3R^(d) and a 6 membered heteroaryl group containing 1 N and substitutedwith 0-3 R^(d); X^(a) is absent or is CH₂ or CH₂CH₂; Y^(a) is absent or0; X¹ is absent or is CH₂ or CH₂CH₂; R⁴ is selected from H, OH, NH₂,CH₃, CH₂OH, and CH₂NH₂; R^(4a) is selected from H, CH₃ and CH₂CH₃;R^(b′) is selected from H, C₁₋₂ alkyl-Q, (CRR′)_(r′)NHR^(a), and(CRR′)_(r)C(O)NHR^(a); R^(c), at each occurrence, is independentlyselected from C₁₋₆ alkyl, OR^(a), Cl, F, Br, I, ═O, CN, NO₂,NR^(a)R^(a′), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a′),R^(a)NC(O)NR^(a)R^(a′), OC(O)NR^(a)R^(a′), R^(a)NC(O)O,S(O)₂NR^(a)R^(a′), NR^(a)S(O)₂R^(a″), NR^(a)S(O)₂NR^(a)R^(a′),OS(O)₂NR^(a)R^(a′), NR^(a)S(O)₂O, S(O)_(p)R^(a″), CF₃, CF₂CF₃, C₅₋₆carbocyclic residue and a 6 membered heterocyclic system containing 1 N;R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl,OR^(a), Cl, F, Br, I, ═O, CN, NO₂, NR^(a)R^(a′), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a′), R^(a)NC(O)NR^(a)R^(a′), OC(O)NR^(a)R^(a′),R^(a)NC(O)O, S(O)₂NR^(a)R^(a′), NR^(a)S(O)₂R^(a″),NR^(a)S(O)₂NR^(a)R^(a′), OS(O)₂NR^(a)R^(a′), NR^(a)S(O)₂O,S(O)_(p)R^(a″), CF₃, CF₂CF₃, C₃₋₆ carbocyclic residue and a 6 memberedheterocyclic system containing 1 N; and, r, at each occurrence, isselected from 0, 1, and 2; r′, at each occurrence, is selected from 1,and 2; and, s, at each occurrence, is selected from 0 and
 1. 5. Acompound according to claim 4, wherein the compound is of formula Ia:


6. A compound according to claim 4, wherein the compound is of formulaIb:

and n is selected from 1, 2, and
 3. 7. A compound is selected from:(1S)-N-hydroxy-2-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)pyrrolidinecarboxamide;(1R)-N-hydroxy-2-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-pyrrolidinecarboxamide;(3S)-N-hydroxy-2,2-dimethyl-4-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-3-thiomorpholinecarboxamide;(2R)-N-hydroxy-1-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-2-piperidinecarboxamide;tert-butyl3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-1-piperazinecarboxylate;N-hydroxy-1-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-2-piperazinecarboxamide;benzyl(3R)-3-[(hydroxyamino)carbonyl]-2-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)tetrahydro-1(2H)-pyridazinecarboxylate;and,(3R)-N-hydroxy-2-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)hexahydro-3-pyridazinecarboxamide;or a pharmaceutically acceptable salt form thereof.
 8. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt form thereof.
 9. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 2 or apharmaceutically acceptable salt form thereof.
 10. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 3 or apharmaceutically acceptable salt form thereof.
 11. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 4 or apharmaceutically acceptable salt form thereof.
 12. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 5 or apharmaceutically acceptable salt form thereof.
 13. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 6 or apharmaceutically acceptable salt form thereof.
 14. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 7 or apharmaceutically acceptable salt form thereof.
 15. A method for treatingan inflammatory disorder, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt form thereof.
 16. A method of treatinga condition or disease mediated by MMPs, TNF, aggrecanase, or acombination thereof in a mammal, comprising: administering to the mammalin need of such treatment a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt form thereof.17. A method of treating a condition or disease wherein the disease orcondition is referred to as rheumatoid arthritis, osteoarthritis,periodontitis, gingivitis, corneal ulceration, solid tumor growth andtumor invasion by secondary metastases, neovascular glaucoma, multiplesclerosis, psoriasis, fever, cardiovascular effects, hemorrhage,coagulation, cachexia, anorexia, alcoholism, acute phase response, acuteinfection, shock, graft versus host reaction, autoimmune disease or HIVinfection, comprising: administering to the mammal in need of suchtreatment a therapeutically effective amount of a compound of claim 1 ora pharmaceutically acceptable salt form thereof.
 18. A method oftreating a condition or disease wherein the disease or condition isreferred to as fever, cardiovascular effects, hemorrhage, coagulation,cachexia, anorexia, alcoholism, acute phase response, acute infection,shock, graft versus host reaction, autoimmune disease or HIV infectionin a mammal comprising administering to the mammal in need of suchtreatment a therapeutically effective amount of a compound of claim 1 ora pharmaceutically acceptable salt form thereof.
 19. A method oftreating a condition or disease wherein the disease or condition isreferred to as rheumatoid arthritis, osteoarthritis, periodontitis,gingivitis, corneal ulceration, solid tumor growth and tumor invasion bysecondary metastases, neovascular glaucoma, multiple sclerosis,psoriasis, fever, cardiovascular effects, hemorrhage, coagulation,cachexia, anorexia, alcoholism, acute phase response, acute infection,shock, graft versus host reaction, autoimmune disease or HIV infection,comprising: administering to the mammal in need of such treatment atherapeutically effective amount of a compound of claim 2 or apharmaceutically acceptable salt form thereof.
 20. A method of treatinga condition or disease wherein the disease or condition is referred toas rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis,corneal ulceration, solid tumor growth and tumor invasion by secondarymetastases, neovascular glaucoma, multiple sclerosis, psoriasis, fever,cardiovascular effects, hemorrhage, coagulation, cachexia, anorexia,alcoholism, acute phase response, acute infection, shock, graft versushost reaction, autoimmune disease or HIV infection, comprising:administering to the mammal in need of such treatment a therapeuticallyeffective amount of a compound of claim 3 or a pharmaceuticallyacceptable salt form thereof.
 21. A method of treating a condition ordisease wherein the disease or condition is referred to as rheumatoidarthritis, osteoarthritis, periodontitis, gingivitis, cornealulceration, solid tumor growth and tumor invasion by secondarymetastases, neovascular glaucoma, multiple sclerosis, psoriasis, fever,cardiovascular effects, hemorrhage, coagulation, cachexia, anorexia,alcoholism, acute phase response, acute infection, shock, graft versushost reaction, autoimmune disease or HIV infection, comprising:administering to the mammal in need of such treatment a therapeuticallyeffective amount of a compound of claim 4 or a pharmaceuticallyacceptable salt form thereof.
 22. A method of treating a condition ordisease wherein the disease or condition is referred to as rheumatoidarthritis, osteoarthritis, periodontitis, gingivitis, cornealulceration, solid tumor growth and tumor invasion by secondarymetastases, neovascular glaucoma, multiple sclerosis, psoriasis, fever,cardiovascular effects, hemorrhage, coagulation, cachexia, anorexia,alcoholism, acute phase response, acute infection, shock, graft versushost reaction, autoimmune disease or HIV infection, comprising:administering to the mammal in need of such treatment a therapeuticallyeffective amount of a compound of claim 5 or a pharmaceuticallyacceptable salt form thereof.
 23. A method of treating a condition ordisease wherein the disease or condition is referred to as rheumatoidarthritis, osteoarthritis, periodontitis, gingivitis, cornealulceration, solid tumor growth and tumor invasion by secondarymetastases, neovascular glaucoma, multiple sclerosis, psoriasis, fever,cardiovascular effects, hemorrhage, coagulation, cachexia, anorexia,alcoholism, acute phase response, acute infection, shock, graft versushost reaction, autoimmune disease or HIV infection, comprising:administering to the mammal in need of such treatment a therapeuticallyeffective amount of a compound of claim 7 or a pharmaceuticallyacceptable salt form thereof.